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  • Review Article
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Engineering approaches for RNA-based and cell-based osteoarthritis therapies

Nature Reviews Rheumatology volume 20, pages 81–100 (2024)Cite this article

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Abstract

Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene levels. However, the pharmacological therapies available remain limited, owing to drug delivery barriers, and consist mainly of broadly immunosuppressive regimens, such as corticosteroids, that provide only short-term palliative benefits and do not alter disease progression. Engineered RNA-based and cell-based therapies developed with synthetic chemistry and biology tools provide promise for future OA treatments with durable, efficacious mechanisms of action that can specifically target the underlying drivers of pathology. This Review highlights emerging classes of RNA-based technologies that hold potential for OA therapies, including small interfering RNA for gene silencing, microRNA and anti-microRNA for multi-gene regulation, mRNA for gene supplementation, and RNA-guided gene-editing platforms such as CRISPR–Cas9. Various cell-engineering strategies are also examined that potentiate disease-dependent, spatiotemporally regulated production of therapeutic molecules, and a conceptual framework is presented for their application as OA treatments. In summary, this Review highlights modern genetic medicines that have been clinically approved for other diseases, in addition to emerging genome and cellular engineering approaches, with the goal of emphasizing their potential as transformative OA treatments.

Key points

  • Osteoarthritis (OA) is a chronic, debilitating disease with limited treatment options, highlighting the need for disease-modifying, gene-targeted OA treatments.

  • RNA-based genetic medicines enable precise targeting of OA-associated pathways, but delivery of the necessary therapeutic components to the joint has historically been challenging.

  • Various preclinical and clinical advances have been made in RNA chemical modification and the delivery of RNA-based medicines for broad application across different diseases.

  • A number of approaches have shown promise in preclinical models of OA, including the use of small interfering RNA, microRNA, anti-microRNA, mRNA and CRISPR–Cas9.

  • Genetically modified cells also have potential in OA; synthetic signalling motifs can be designed to rewire native signalling pathways or implement specified responses to user-selected inputs (such as inflammatory signals).

  • RNA-guided and gene circuit-guided technologies can enable the engineering of cell therapies that recognize and respond to specific pathological cues.

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Fig. 1: Pathophysiological features of OA and considerations for delivering RNA-based and cellular therapeutics.
Fig. 2: Key mechanisms of therapeutic RNA.
Fig. 3: Key RNA drug delivery strategies and modifications.
Fig. 4: Synthetic gene circuit designs for OA-specific engineered cell therapies.

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References

  1. Hsieh, J. L. et al. Intraarticular gene transfer of thrombospondin-1 suppresses the disease progression of experimental osteoarthritis. J. Orthop. Res. 28, 1300–1306 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Rabie, M. A. et al. Intra-articular injection of rAAV-hFGF-2 ameliorates monosodium iodoacetate-induced osteoarthritis in rats via inhibiting TLR-4 signaling and activating TIMP-1. Toxicol. Appl. Pharmacol. 459, 116361 (2023).

    Article  CAS  PubMed  Google Scholar 

  3. Chen, B., Qin, J., Wang, H., Magdalou, J. & Chen, L. Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp. Mol. Med. 42, 684–695 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Frisbie, D. D., Ghivizzani, S. C., Robbins, P. D., Evans, C. H. & McIlwraith, C. W. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther. 9, 12–20 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Schrenker, S. et al. In vivo rAAV-mediated human TGF-β overexpression reduces perifocal osteoarthritis and improves osteochondral repair in a large animal model at one year. Osteoarthritis Cartilage 31, 467–481 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Maihöfer, J. et al. Hydrogel-guided, rAAV-mediated IGF-I overexpression enables long-term cartilage repair and protection against perifocal osteoarthritis in a large-animal full-thickness chondral defect model at one year in vivo. Adv. Mater. 33, e2008451 (2021).

    Article  PubMed  Google Scholar 

  7. Lange, C. et al. rAAV-mediated sox9 overexpression improves the repair of osteochondral defects in a clinically relevant large animal model over time in vivo and reduces perifocal osteoarthritic changes. Am. J. Sports Med. 49, 3696–3707 (2021).

    Article  PubMed  Google Scholar 

  8. Riyad, J. M. & Weber, T. Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions. Gene Ther. 28, 683–696 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamilton, B. A. & Wright, J. F. Challenges posed by immune responses to AAV vectors: addressing root causes. Front. Immunol. 12, 675897 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mehta, S., He, T. & Bajpayee, A. G. Recent advances in targeted drug delivery for treatment of osteoarthritis. Curr. Opin. Rheumatol. 33, 94–109 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Neogi, T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage 21, 1145–1153 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Plotnikoff, R. et al. Osteoarthritis prevalence and modifiable factors: a population study. BMC Public. Health 15, 1195 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Thomas, A. C., Hubbard-Turner, T., Wikstrom, E. A. & Palmieri-Smith, R. M. Epidemiology of posttraumatic osteoarthritis. J. Athl. Train. 52, 491–496 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Loeser, R. F. The role of aging in the development of osteoarthritis. Trans. Am. Clin. Climatol. Assoc. 128, 44–54 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boer, C. G. et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell 184, 6003–6005 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu, C. L., Kimmerling, K. A., Little, D. & Guilak, F. Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair. Sci. Rep. 7, 44315 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mitchell, P. G. et al. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97, 761–768 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Glasson, S. S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Thomas, C. M., Fuller, C. J., Whittles, C. E. & Sharif, M. Chondrocyte death by apoptosis is associated with cartilage matrix degradation. Osteoarthritis Cartilage 15, 27–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Sofat, N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int. J. Exp. Pathol. 90, 463–479 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lanas, A., Tornero, J. & Zamorano, J. L. Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann. Rheum. Dis. 69, 1453 (2010).

    Article  PubMed  Google Scholar 

  24. McAlindon, T. E. et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 317, 1967–1975 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cooper, C. et al. Use of intraarticular hyaluronic acid in the management of knee osteoarthritis in clinical practice. Arthritis Care Res. 69, 1287–1296 (2017).

    Article  Google Scholar 

  26. O’Connell, B., Wragg, N. M. & Wilson, S. L. The use of PRP injections in the management of knee osteoarthritis. Cell Tissue Res. 376, 143–152 (2019).

    Article  PubMed  Google Scholar 

  27. Shariatzadeh, M., Song, J. & Wilson, S. L. The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis. Cell Tissue Res. 378, 399–410 (2019).

    Article  PubMed  Google Scholar 

  28. Montesi, L. et al. Long-term weight loss maintenance for obesity: a multidisciplinary approach. Diabetes, Metab. Syndr. Obes. 9, 37–46 (2016).

    PubMed  Google Scholar 

  29. Vincent, H. K., Heywood, K., Connelly, J. & Hurley, R. W. Obesity and weight loss in the treatment and prevention of osteoarthritis. PM R 4, S59–S67 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cabassi, A. et al. Non-steroidal anti-inflammatory drug effects on renal and cardiovascular function: from physiology to clinical practice. Eur. J. Prev. Cardiol. 27, 850–867 (2020).

    Article  PubMed  Google Scholar 

  31. Ong, K. L., Runa, M., Lau, E. & Altman, R. D. Cost-of-illness of knee osteoarthritis: potential cost savings by not undergoing arthroplasty within the first 2 years. Clinicoecon. Outcomes Res. 11, 245–255 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Schreurs, B. W. & Hannink, G. Total joint arthroplasty in younger patients: heading for trouble? Lancet 389, 1374–1375 (2017).

    Article  PubMed  Google Scholar 

  33. Thanh Le, T. et al. The COVID-19 vaccine development landscape. Nat. Rev. Drug. Discov. 19, 305–306 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Kingwell, K. First CRISPR therapy seeks landmark approval. Nat. Rev. Drug Discov. 22, 339–341 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Egli, M. & Manoharan, M. Chemistry, structure and function of approved oligonucleotide therapeutics. Nucleic Acids Res. 51, 2529–2573 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Crooke, S. T., Baker, B. F., Crooke, R. M. & Liang, X.-H. Antisense technology: an overview and prospectus. Nat. Rev. Drug. Discov. 20, 427–453 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Nakamura, A., Ali, S. A. & Kapoor, M. Antisense oligonucleotide-based therapies for the treatment of osteoarthritis: opportunities and roadblocks. Bone 138, 115461 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Hickerson, R. P. et al. Stability study of unmodified siRNA and relevance to clinical use. Oligonucleotides 18, 345–354 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, J., Lu, Z., Wientjes, M. G. & Au, J. L. S. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 12, 492–503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Meng, Z. & Lu, M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front. Immunol. 8, 331 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hu, B. et al. Therapeutic siRNA: state of the art. Signal. Transduct. Target. Ther. 5, 101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lima, J. F., Cerqueira, L., Figueiredo, C., Oliveira, C. & Azevedo, N. F. Anti-miRNA oligonucleotides: a comprehensive guide for design. RNA Biol. 15, 338–352 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Filippova, J., Matveeva, A., Zhuravlev, E. & Stepanov, G. Guide RNA modification as a way to improve CRISPR/Cas9-based genome-editing systems. Biochimie 167, 49–60 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Chiu, Y.-L. & Rana, T. M. siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shaw, J.-P., Kent, K., Bird, J., Fishback, J. & Froehler, B. Modified deoxyoligonucleotides stable to exonuclease degradation in serum. Nucleic Acids Res. 19, 747–750 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kaur, H., Babu, B. R. & Maiti, S. Perspectives on chemistry and therapeutic applications of locked nucleic acid (LNA). Chem. Rev. 107, 4672–4697 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Quijano, E., Bahal, R., Ricciardi, A., Saltzman, W. M. & Glazer, P. M. Therapeutic peptide nucleic acids: principles, limitations, and opportunities. Yale J. Biol. Med. 90, 583–598 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Brown, K. M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat. Biotechnol. 40, 1500–1508 (2022).

    Article  CAS  PubMed  Google Scholar 

  50. Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).

    Article  PubMed  Google Scholar 

  53. Peacock, H., Kannan, A., Beal, P. A. & Burrows, C. J. Chemical modification of siRNA bases to probe and enhance RNA interference. J. Org. Chem. 76, 7295–7300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ji, M.-L. et al. Precise targeting of miR-141/200c cluster in chondrocytes attenuates osteoarthritis development. Ann. Rheum. Dis. 80, 356–366 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Bedingfield, S. K. et al. Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage. Nat. Biomed. Eng. 5, 1069–1083 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cho, H., Pinkhassik, E., David, V., Stuart, J. M. & Hasty, K. A. Detection of early cartilage damage using targeted nanosomes in a post-traumatic osteoarthritis mouse model. Nanomed. Nanotechnol. Biol. Med. 11, 939–946 (2015).

    Article  CAS  Google Scholar 

  57. Rothenfluh, D. A., Bermudez, H., O’Neil, C. P. & Hubbell, J. A. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat. Mater. 7, 248–254 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Pradal, J. et al. Effect of particle size on the biodistribution of nano- and microparticles following intra-articular injection in mice. Int. J. Pharm. 498, 119–129 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Chen, Z. et al. Development of nanoparticles-in-microparticles system for improved local retention after intra-articular injection. Drug. Deliv. 21, 342–350 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Bajpayee, A. G., Wong, C. R., Bawendi, M. G., Frank, E. H. & Grodzinsky, A. J. Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis. Biomaterials 35, 538–549 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Bedingfield, S. K. et al. Top-down fabricated microplates for prolonged, intra-articular matrix metalloproteinase 13 siRNA nanocarrier delivery to reduce post-traumatic osteoarthritis. ACS Nano 15, 14475–14491 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pradal, J. et al. Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system. Eur. J. Pharm. Biopharm. 93, 110–117 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Tan, Z. et al. Polycation architecture and assembly direct successful gene delivery: micelleplexes outperform polyplexes via optimal DNA packaging. J. Am. Chem. Soc. 141, 15804–15817 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, Q. et al. Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy. Biomaterials 122, 10–22 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Johnston, B. M., Grodzinsky, A. J. & Hammond, P. T. Charge shielding effects of PEG bound to NH2-terminated PAMAM dendrimers — an experimental approach. Soft Matter 19, 3033–3046 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fletcher, R. B. et al. Nonviral in vivo delivery of CRISPR-Cas9 using protein-agnostic, high-loading porous silicon and polymer nanoparticles. ACS Nano 17, 16412–16431 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, M. J. et al. Notch1 targeting siRNA delivery nanoparticles for rheumatoid arthritis therapy. J. Control. Release 216, 140–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Jin, H. et al. Delivery of microRNA-10b with polylysine nanoparticles for inhibition of breast cancer cell wound healing. Breast Cancer 6, BCBCR–S8513 (2012).

    Google Scholar 

  69. Ledo, A. M. et al. Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. J. Control. Release 295, 60–73 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Zou, L., Peng, Q., Wang, P. & Zhou, B. Progress in research and application of HIV-1 TAT-derived cell-penetrating peptide. J. Membr. Biol. 250, 115–122 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Lou, B., Lau, C. Y. J., Hennink, W. E. & Mastrobattista, E. Preparation of mRNA polyplexes with post-conjugated endosome-disruptive peptides. Methods Mol. Biol. 2355, 275–286 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Tai, W. & Gao, X. Functional peptides for siRNA delivery. Adv. Drug. Deliv. Rev. 110-111, 157–168 (2017).

    Article  CAS  PubMed  Google Scholar 

  73. Hou, K. K., Pan, H., Lanza, G. M. & Wickline, S. A. Melittin derived peptides for nanoparticle based siRNA transfection. Biomaterials 34, 3110–3119 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yan, H. et al. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc. Natl Acad. Sci. USA 113, E6199–E6208 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Duan, X. et al. Amelioration of posttraumatic osteoarthritis in mice using intraarticular silencing of periostin via nanoparticle-based small interfering RNA. Arthritis Rheumatol. 73, 2249–2260 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jin, Y. et al. Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. Int. J. Oral. Sci. 14, 34 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pi, Y. et al. Targeted delivery of non-viral vectors to cartilage in vivo using a chondrocyte-homing peptide identified by phage display. Biomaterials 32, 6324–6332 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Li, H. et al. Dual MMP7-proximity-activated and folate receptor-targeted nanoparticles for siRNA delivery. Biomacromolecules 16, 192–201 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Li, H. et al. Matrix metalloproteinase responsive, proximity-activated polymeric nanoparticles for siRNA delivery. Adv. Funct. Mater. 23, 3040–3052 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liang, Y. et al. Chondrocyte-targeted microRNA delivery by engineered exosomes toward a cell-free osteoarthritis therapy. ACS Appl. Mater. Interfaces 12, 36938–36947 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Dimitriadis, G. J. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature 274, 923–924 (1978).

    Article  CAS  PubMed  Google Scholar 

  82. Felgner, P. L. et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc. Natl Acad. Sci. USA 84, 7413–7417 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang, Y. B., Sun, C. Z., Wang, C., Jankovic, K. E. & Dong, Y. Z. Lipids and lipid derivatives for RNA delivery. Chem. Rev. 121, 12181–12277 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kou, L. et al. Biomaterial-engineered intra-articular drug delivery systems for osteoarthritis therapy. Drug. Deliv. 26, 870–885 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Hoy, S. M. Patisiran: first global approval. Drugs 78, 1625–1631 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Dai, B. et al. Blockage of osteopontin-integrin beta3 signaling in infrapatellar fat pad attenuates osteoarthritis in mice. Adv. Sci. 10, e2300897 (2023).

    Article  Google Scholar 

  88. Pi, Y. et al. Intra-articular delivery of anti-Hif-2ɑ siRNA by chondrocyte-homing nanoparticles to prevent cartilage degeneration in arthritic mice. Gene Ther. 22, 439–448 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Gong, Y. et al. Inhibition of YAP with siRNA prevents cartilage degradation and ameliorates osteoarthritis development. J. Mol. Med. 97, 103–114 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Lin, L., Zhu, S., Huang, H., Wu, L. P. & Huang, J. Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy. Mol. Ther. Nucleic Acids 31, 88–104 (2023).

    Article  CAS  PubMed  Google Scholar 

  91. Hoshi, H. et al. Effect of inhibiting MMP13 and ADAMTS5 by intra-articular injection of small interfering RNA in a surgically induced osteoarthritis model of mice. Cell Tissue Res. 368, 379–387 (2017).

    Article  CAS  PubMed  Google Scholar 

  92. Akagi, R. et al. Effective knock down of matrix metalloproteinase-13 by an intra-articular injection of small interfering RNA (siRNA) in a murine surgically-induced osteoarthritis model. J. Orthop. Res. 32, 1175–1180 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Nakagawa, R. et al. Single vs. repeated matrix metalloproteinase-13 knockdown with intra-articular short interfering RNA administration in a murine osteoarthritis model. Connect. Tissue Res. 60, 335–343 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Oo, W. M., Liu, X. & Hunter, D. J. Pharmacodynamics, efficacy, safety and administration of intra-articular therapies for knee osteoarthritis. Expert. Opin. Drug. Metab. Toxicol. 15, 1021–1032 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Hoogenboezem, E. N. et al. Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-targeted cancer therapy. Preprint at bioRxiv https://doi.org/10.1101/2023.02.14.528574 (2023).

  96. Sarett, S. M. et al. Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing. Proc. Natl Acad. Sci. USA 114, E6490–E6497 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Colazo, J. M. et al. Albumin-binding RNAi conjugate for carrier free treatment of arthritis. Preprint at bioRxiv https://doi.org/10.1101/2023.05.31.542971 (2023).

  98. O’Brien, J., Hayder, H., Zayed, Y. & Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 9, 402 (2018).

    Article  Google Scholar 

  99. Diener, C., Keller, A. & Meese, E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 38, 613–626 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Zhu, J. et al. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Sci. Adv. 8, eabk0011 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang, M., Lygrisse, K. & Wang, J. Role of MicroRNA in osteoarthritis. J. Arthritis 6, 239 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Baek, D. et al. Inhibition of miR-449a promotes cartilage regeneration and prevents progression of osteoarthritis in in vivo rat models. Mol. Ther. Nucleic Acids 13, 322–333 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lolli, A. et al. Hydrogel-based delivery of antimiR-221 enhances cartilage regeneration by endogenous cells. J. Control. Release 309, 220–230 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Anderson, B. A. & McAlinden, A. miR‐483 targets SMAD4 to suppress chondrogenic differentiation of human mesenchymal stem cells. J. Orthop. Res. 35, 2369–2377 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nakamura, A. et al. microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints. Ann. Rheum. Dis. 78, 111–121 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Zhang, L. et al. Yeast cell wall particle mediated nanotube-RNA delivery system loaded with miR365 antagomir for post-traumatic osteoarthritis therapy via oral route. Theranostics 10, 8479 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yamamoto, A., Kormann, M., Rosenecker, J. & Rudolph, C. Current prospects for mRNA gene delivery. Eur. J. Pharm. Biopharm. 71, 484–489 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Aini, H. et al. Messenger RNA delivery of a cartilage-anabolic transcription factor as a disease-modifying strategy for osteoarthritis treatment. Sci. Rep. 6, 18743 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yan, H. et al. Induction of WNT16 via peptide-mRNA nanoparticle-based delivery maintains cartilage homeostasis. Pharmaceutics 12, 73 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Deng, J. et al. Anti-Inflammatory therapy for temporomandibular joint osteoarthritis using mRNA medicine encoding interleukin-1 receptor antagonist. Pharmaceutics 14 (2022).

  111. Yip, B. H. Recent advances in CRISPR/Cas9 delivery strategies. Biomolecules 10, 839 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hsu, P. D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827–832 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Jaskolka, M. C. et al. Exploratory safety profile of EDIT-101, a first-in-human in vivo CRISPR gene editing therapy for CEP290-related retinal degeneration. Investig. Ophthalmol. Vis. Sci. 63, 2836–A0352 (2022).

    Google Scholar 

  116. Gillmore, J. D. et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 385, 493–502 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Frangoul, H. et al. Safety and efficacy of CTX001 in patients with transfusion-dependent β-thalassemia and sickle cell disease: early results from the climb THAL-111 and climb SCD-121 studies of autologous CRISPR-CAS9-modified CD34+ hematopoietic stem and progenitor cells. Blood 136, 3–4 (2020).

    Article  Google Scholar 

  118. Dimitri, A., Herbst, F. & Fraietta, J. A. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing. Mol. Cancer 21, 78 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wong, C. UK first to approve CRISPR treatment for diseases: what you need to know. Nature 623, 676–677 (2023).

    Article  CAS  PubMed  Google Scholar 

  120. Sheridan, C. The world’s first CRISPR therapy is approved: who will receive it? Nat. Biotechnol. https://doi.org/10.1038/d41587-023-00016-6 (2023).

  121. Naeem, M., Majeed, S., Hoque, M. Z. & Ahmad, I. Latest developed strategies to minimize the off-target effects in CRISPR-Cas-mediated genome editing. Cells 9, 1608 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Han, H. A., Pang, J. K. S. & Soh, B.-S. Mitigating off-target effects in CRISPR/Cas9-mediated in vivo gene editing. J. Mol. Med. 98, 615–632 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Höijer, I. et al. CRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations. Nat. Commun. 13, 627 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Mehta, A. & Merkel, O. M. Immunogenicity of Cas9 protein. J. Pharm. Sci. 109, 62–67 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Lino, C. A., Harper, J. C., Carney, J. P. & Timlin, J. A. Delivering CRISPR: a review of the challenges and approaches. Drug. Deliv. 25, 1234–1257 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nelson, C. E. et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat. Med. 25, 427–432 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Doudna, J. A. The promise and challenge of therapeutic genome editing. Nature 578, 229–236 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zuris, J. A. et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat. Biotechnol. 33, 73–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Finn, J. D. et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 22, 2227–2235 (2018).

    Article  CAS  PubMed  Google Scholar 

  130. Wang, M. et al. Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles. Proc. Natl Acad. Sci. USA 113, 2868–2873 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, Z. et al. Cationic polymer-mediated CRISPR/Cas9 plasmid delivery for genome editing. Macromol. Rapid Commun. 40, e1800068 (2019).

    Article  PubMed  Google Scholar 

  132. Xu, C. et al. Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases. Nat. Commun. 9, 4092 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Lee, K. et al. Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA. Nat. Biomed. Eng. 1, 889–901 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mout, R. et al. Direct cytosolic delivery of CRISPR/Cas9-ribonucleoprotein for efficient gene editing. ACS Nano 11, 2452–2458 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wilbie, D., Walther, J. & Mastrobattista, E. Delivery aspects of CRISPR/Cas for in vivo genome editing. Acc. Chem. Res. 52, 1555–1564 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Seidl, C. I., Fulga, T. A. & Murphy, C. L. CRISPR-Cas9 targeting of MMP13 in human chondrocytes leads to significantly reduced levels of the metalloproteinase and enhanced type II collagen accumulation. Osteoarthritis Cartilage 27, 140–147 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Liang, Y. et al. Chondrocyte-specific genomic editing enabled by hybrid exosomes for osteoarthritis treatment. Theranostics 12, 4866–4878 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kim, S. H. et al. Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials. Arch. Orthop. Trauma Surg. 139, 971–980 (2019).

    Article  PubMed  Google Scholar 

  139. Shah, S., Otsuka, T., Bhattacharjee, M. & Laurencin, C. T. Minimally invasive cellular therapies for osteoarthritis treatment. Regen. Eng. Transl. Med. 7, 76–90 (2021).

    Article  Google Scholar 

  140. Kay, J. D. et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus. J. Gene Med. 11, 605–614 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Brunger, J. M. et al. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc. Natl Acad. Sci. USA 111, E798–E806 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Madry, H. et al. Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther. 12, 1171–1179 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Raisin, S., Belamie, E. & Morille, M. Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. Biomaterials 104, 223–237 (2016).

    Article  CAS  PubMed  Google Scholar 

  144. Raftery, R. M., Gonzalez Vazquez, A. G., Chen, G. & O’Brien, F. J. Activation of the SOX-5, SOX-6, and SOX-9 trio of transcription factors using a gene-activated scaffold stimulates mesenchymal stromal cell chondrogenesis and inhibits endochondral ossification. Adv. Healthc. Mater. 9, e1901827 (2020).

    Article  PubMed  Google Scholar 

  145. Uzieliene, I., Kalvaityte, U., Bernotiene, E. & Mobasheri, A. Non-viral gene therapy for osteoarthritis. Front. Bioeng. Biotechnol. 8, 618399 (2020).

    Article  PubMed  Google Scholar 

  146. Guilak, F. et al. Designer stem cells: genome engineering and the next generation of cell-based therapies. J. Orthop. Res. 37, 1287–1293 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Bhattacharyya, R. P., Reményi, A., Yeh, B. J. & Lim, W. A. Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits. Annu. Rev. Biochem. 75, 655–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  149. Manhas, J., Edelstein, H. I., Leonard, J. N. & Morsut, L. The evolution of synthetic receptor systems. Nat. Chem. Biol. 18, 244–255 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Stapornwongkul, K. S., de Gennes, M., Cocconi, L., Salbreux, G. & Vincent, J. P. Patterning and growth control in vivo by an engineered GFP gradient. Science 370, 321–327 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Barnea, G. et al. The genetic design of signaling cascades to record receptor activation. Proc. Natl Acad. Sci. USA 105, 64–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  152. Scheller, L., Strittmatter, T., Fuchs, D., Bojar, D. & Fussenegger, M. Generalized extracellular molecule sensor platform for programming cellular behavior. Nat. Chem. Biol. 14, 723–729 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Chung, H. K. et al. A compact synthetic pathway rewires cancer signaling to therapeutic effector release. Science 364, eaat6982 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Gao, X. J., Chong, L. S., Kim, M. S. & Elowitz, M. B. Programmable protein circuits in living cells. Science 361, 1252–1258 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fischbach, M. A., Bluestone, J. A. & Lim, W. A. Cell-based therapeutics: the next pillar of medicine. Sci. Transl. Med. 5, 179ps177 (2013).

    Article  Google Scholar 

  156. Lee, J. C., Walton, B. L., Hamann, C. A. & Brunger, J. M. Synthetic regulation of multicellular systems for regenerative engineering. Curr. Opin. Biomed. Eng. 16, 42–51 (2020).

    Article  Google Scholar 

  157. Schukur, L., Geering, B., Charpin-El Hamri, G. & Fussenegger, M. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Sci. Transl. Med. 7, 318ra201 (2015).

    Article  PubMed  Google Scholar 

  158. Smole, A., Lainšček, D., Bezeljak, U., Horvat, S. & Jerala, R. A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation. Mol. Ther. 25, 102–119 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Krawczyk, K., Scheller, L., Kim, H. & Fussenegger, M. Rewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming. Nat. Commun. 11, 608 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Miagkov, A. V., Varley, A. W., Munford, R. S. & Makarov, S. S. Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints. J. Clin. Invest. 109, 1223–1229 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Pferdehirt, L., Ross, A. K., Brunger, J. M. & Guilak, F. A synthetic gene circuit for self-regulating delivery of biologic drugs in engineered tissues. Tissue Eng. Part. A 25, 809–820 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Gabner, S. et al. Cytokine-induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment. J. Gene Med. 20, e3021 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Rachakonda, P. S., Rai, M. F. & Schmidt, M. F. Application of inflammation-responsive promoter for an in vitro arthritis model. Arthritis Rheum. 58, 2088–2097 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. van de Loo, F. A. et al. An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint. Gene Ther. 11, 581–590 (2004).

    Article  PubMed  Google Scholar 

  165. Brunger, J. M., Zutshi, A., Willard, V. P., Gersbach, C. A. & Guilak, F. Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs. Stem Cell Rep. 8, 1202–1213 (2017).

    Article  CAS  Google Scholar 

  166. Choi, Y. R. et al. A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery. Sci. Adv. 7, eabj1414 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Collins, K. H. et al. Hydrogel encapsulation of genome-engineered stem cells for long-term self-regulating anti-cytokine therapy. Gels 9, 169 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Farhang, N. et al. CRISPR-based epigenome editing of cytokine receptors for the promotion of cell survival and tissue deposition in inflammatory environments. Tissue Eng. Part. A 23, 738–749 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Farhang, N. et al. Lentiviral CRISPR epigenome editing of inflammatory receptors as a gene therapy strategy for disc degeneration. Hum. Gene Ther. 30, 1161–1175 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Margolin, J. F. et al. Krüppel-associated boxes are potent transcriptional repression domains. Proc. Natl Acad. Sci. USA 91, 4509–4513 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442–451 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Qi, L. S. et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Nuñez, J. K. et al. Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell 184, 2503–2519.e2517 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Nims, R. J. et al. A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Sci. Adv. 7, eabd9858 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Milone, M. C. et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 17, 1453–1464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Sadelain, M., Brentjens, R. & Rivière, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Fan, A. et al. Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression. Bone Res. 11, 3 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Swahn, H. et al. Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus. Ann. Rheum. Dis. 82, 403–415 (2023).

    Article  CAS  PubMed  Google Scholar 

  182. Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Qian, Z. et al. Engineered regulatory T cells coexpressing MHC class II: peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis. J. Immunol. 190, 5382–5391 (2013).

    Article  CAS  PubMed  Google Scholar 

  184. Whittington, K. B. et al. CD8+ T cells expressing an HLA-DR1 chimeric antigen receptor target autoimmune CD4+ T cells in an antigen-specific manner and inhibit the development of autoimmune arthritis. J. Immunol. 208, 16–26 (2022).

    Article  CAS  PubMed  Google Scholar 

  185. Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Roth, T. L. et al. Pooled knockin targeting for genome engineering of cellular immunotherapies. Cell 181, 728–744.e721 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Luca, V. C. et al. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 355, 1320–1324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Gordon, W. R. et al. Mechanical allostery: evidence for a force requirement in the proteolytic activation of notch. Dev. Cell 33, 729–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164, 780–791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Zhu, I. et al. Modular design of synthetic receptors for programmed gene regulation in cell therapies. Cell 185, 1431–1443.e1416 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Das, T. A., Tenenbaum, L. & Berkhout, B. Tet-on systems for doxycycline-inducible gene expression. Curr. Gene Ther. 16, 156–167 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Choe, J. H. et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci. Transl. Med. 13, eabe7378 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ruffo, E. et al. Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting. Nat. Commun. 14, 2463 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Toda, S., Blauch, L. R., Tang, S. K. Y., Morsut, L. & Lim, W. A. Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 361, 156–162 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lee, J. C. et al. Instructional materials that control cellular activity through synthetic Notch receptors. Biomaterials 297, 122099 (2023).

    Article  CAS  PubMed  Google Scholar 

  198. Zhang, S. et al. Monitoring of cell-cell communication and contact history in mammals. Science 378, eabo5503 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Malaguti, M. et al. SyNPL: synthetic notch pluripotent cell lines to monitor and manipulate cell interactions in vitro and in vivo. Development 149, dev200226 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Knights, A. J. et al. Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis. Ann. Rheum. Dis. 82, 272–282 (2023).

    Article  CAS  PubMed  Google Scholar 

  201. Bradley, P. X. et al. The interplay of biomechanical and biological changes following meniscus injury. Curr. Rheumatol. Rep. 25, 35–46 (2023).

    Article  CAS  PubMed  Google Scholar 

  202. Belluzzi, E. et al. Infrapatellar fat pad gene expression and protein production in patients with and without osteoarthritis. Int. J. Mol. Sci. 21, 6016 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Collins, K. H. et al. Adipose tissue is a critical regulator of osteoarthritis. Proc. Natl Acad. Sci. USA 118, e2021096118 (2021).

    Article  CAS  PubMed  Google Scholar 

  204. Zhu, X., Chan, Y. T., Yung, P. S. H., Tuan, R. S. & Jiang, Y. Subchondral bone remodeling: a therapeutic target for osteoarthritis. Front. Cell Dev. Biol. 8, 607764 (2020).

    Article  PubMed  Google Scholar 

  205. Cohen, S. et al. Interim phase 1 part A results for ALN-APP, the first investigational RNAi therapeutic in development for Alzheimer’s disease. Alzheimers Dementia 19, e082650 (2023).

    Article  Google Scholar 

  206. Kivitz, A. et al. Clinical assessment of pain, tolerability, and preference of an autoinjection pen versus a prefilled syringe for patient self-administration of the fully human, monoclonal antibody adalimumab: the TOUCH trial. Clin. Therapeutics 28, 1619–1629 (2006).

    Article  CAS  Google Scholar 

  207. Bombardieri, S. et al. Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology 46, 1191–1199 (2007).

    Article  CAS  PubMed  Google Scholar 

  208. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Gaudelli, N. M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Porto, E. M., Komor, A. C., Slaymaker, I. M. & Yeo, G. W. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug. Discov. 19, 839–859 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Chen, P. J. et al. Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell 184, 5635–5652.e5629 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Huang, Z. & Liu, G. Current advancement in the application of prime editing. Front. Bioeng. Biotechnol. 11, 1039315 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Wang, B. et al. A low dose cell therapy system for treating osteoarthritis: in vivo study and in vitro mechanistic investigations. Bioact. Mater. 7, 478–490 (2022).

    CAS  PubMed  Google Scholar 

  215. Thorup, A.-S. et al. ROR2 blockade as a therapy for osteoarthritis. Sci. Transl. Med. 12, eaax3063 (2020).

    Article  CAS  PubMed  Google Scholar 

  216. Kucharski, A. et al. 4-Aminobutyrate aminotransferase regulates chondrocyte homeostasis and can be targeted using peptide-siRNA nanoparticles to attenuate osteoarthritis in a murine injury model. Osteoarthritis Cartilage 29, S13–S14 (2021).

    Article  Google Scholar 

  217. Wang, S. et al. A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle-RNAi delivery system. Int. J. Nanomed. 13, 617–631 (2018).

    Article  CAS  Google Scholar 

  218. Shin, H. J. et al. p47phox siRNA-Loaded PLGA nanoparticles suppress ROS/oxidative stress-induced chondrocyte damage in osteoarthritis. Polymers 12, 443 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Park, H. et al. p16INK4a-siRNA nanoparticles attenuate cartilage degeneration in osteoarthritis by inhibiting inflammation in fibroblast-like synoviocytes. Biomater. Sci. 10, 3223–3235 (2022).

    Article  CAS  PubMed  Google Scholar 

  220. Kucharski, A. et al. Nanoparticle based dnmt3b gene therapy attenuates arthritis progression in a murine injury model. Osteoarthritis Cartilage 31, 695–696 (2023).

    Article  Google Scholar 

  221. Chen, H. et al. Urchin-like ceria nanoparticles for enhanced gene therapy of osteoarthritis. Sci. Adv. 9, eadf0988 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Zhao, L. et al. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann. Rheum. Dis. 78, 676–682 (2019).

    Article  CAS  PubMed  Google Scholar 

  223. Fan, Y., Zhao, L., Lai, Y., Lu, K. & Huang, J. CRISPR-Cas9-mediated loss of function of beta-catenin attenuates intervertebral disc degeneration. Mol. Ther. Nucleic Acids 28, 387–396 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10, 973–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Glass, K. A. et al. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials 35, 5921–5931 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Schwarz, K. A., Daringer, N. M., Dolberg, T. B. & Leonard, J. N. Rewiring human cellular input-output using modular extracellular sensors. Nat. Chem. Biol. 13, 202–209 (2017).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work of the authors is supported by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH NIAMS) R21 AR079245 (C.L.D., J.M.B., R.D., B.L.W.), R21 AR078636 (C.L.D., J.M.C., N.F.), R21 AR079683 (C.L.D., J.M.B., B.L.W.), and R01 AR078666 (C.L.D., R.D., C.R.D.), as well as the NIH National Institute of Biomedical Imaging and Bioengineering (T32-EB021937, C.R.D.). Additional support was provided by the Arthritis National Research Foundation Judy E. Green Valiant Women’s Fellowship. J.M.C is supported by NIGMS of the National Institutes of Health under award number T32GM007347, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Rheumatology Research Foundation (RRF). 

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  1. These authors contributed equally: Carlisle R. DeJulius, Bonnie L. Walton.

Authors and Affiliations

  1. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA

    Carlisle R. DeJulius, Bonnie L. Walton, Juan M. Colazo, Richard d’Arcy, Nora Francini, Jonathan M. Brunger & Craig L. Duvall

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  1. Carlisle R. DeJulius
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Contributions

All authors researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. C.R.D., C.L.D., B.L.W., J.M.C., R.D., N.F. and J.M.B. contributed substantially to discussion of the content.

Corresponding authors

Correspondence to Jonathan M. Brunger or Craig L. Duvall.

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Competing interests

C.L.D., C.R.D., and R.D. hold patents related to drug delivery (US20170096517A1 (C.L.D.); WO2018213361A1 (C.L.D.); WO2019068098A1 (C.L.D., C.R.D.); US20180064749A1 (C.L.D.); WO2023059833A1 (C.L.D. and R.D.); WO2023034561A2 (C.L.D.); US2023/018982 (C.L.D., C.R.D. and R.D.; filed)). J.M.B., B.L.W., and C.L.D. hold patents related to cell engineering (US-11319555-B2 (J.M.B.); US-10954513-B2 (J.M.B.); US-20230295262-A1 (J.M.B., B.L.W. and C.L.D.; filed)). These patents reflect long-standing interest and innovation in the fields of RNA delivery and cell design.

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Glossary

Agomir

A synthetic, stabilized RNA molecule designed to mimic a mature microRNA. Chemical stabilizations on the antisense strand include phophorothioate bonds at the 5′ and 3′ ends, full-length 2′ OMe ribose modifications, and 3′ cholesterol strand end conjugation.

Anti-microRNA

Short (19–22 base-pairs), single-stranded synthetic RNA that binds microRNA to block binding to target mRNA.

Antisense oligonucleotide

A short oligonucleotide that changes gene expression by base-pairing with RNA and triggering different post-hybridization mechanisms.

Base editors

A genome-editing technology capable of changing DNA sequences without generating a double-stranded break; contains a Cas9 nickase fused to nucleoside deaminase for the chemical modification of bases located within complementary sequences to a complexed gRNA sequence; typically used for single nucleotide changes.

Colloidal stability

For nanoparticles, refers to their resistance to aggregation.

Endosomal escape

Nanomoaterials typically enter cells via endosomes (intracellular trafficking vesicles), but are usually targeting the cellular cytosol or nucleus. Therefore, a mechanism to exit the endosome after uptake is essential for activity.

Endosomal proton sponge effect

Refers to the phenomenon in which pH-responsive materials, including certain polymers and lipids, accumulate protons in the endosome, resulting in swelling and eventual rupture of endosomes.

Guide RNA

RNA that loads into the CRISPR proteins and directs the ribonuclear protein to a complementary nucleic acid sequence; in the case of the CRISPR–Cas9 ribonuclear protein complex, this process leads to a double-stranded break in the target nucleic acid strand.

Helper lipids

Lipids that are incorporated into lipid nanoparticles or liposomes to improve stability and fluidity.

Hydrogels

Three-dimensional polymeric networks that absorb a large amount of water; can be adapted to a wide range of mechanical properties, polymer compositions and fabrication methods.

Indel

A term referring to an insertion and/or deletion of nucleotides from a DNA sequence.

Locked nucleic acid

A synthetic structural modification to RNA ribose in which a methylene bridge ‘locks’ the nucleoside in a particular conformation, increasing its stability; this modification can also increase target-binding affinity.

Messenger RNA

Long (hundreds to thousands of base-pairs), single-stranded RNA that is translated to proteins.

Micelleplexes

Drug delivery vehicles formed from block copolymers that have amphiphilic properties (that is, contain both hydrophobic and hydrophilic blocks) and cationic properties, which can self-assemble for nucleic acid delivery.

Microparticles

Materials that are typically >1 µm; can be spherical, porous or templated to a desired shape; typically formulated from polymers.

MicroRNA

Short (19–22 base-pairs), double-stranded non-coding RNA that binds mRNA and affects translation of these RNAs, either through targeted degradation or through increased translation. Typically affects multiple related messenger RNAs.

Nanoparticles

Materials that are typically 1–500 nm in diameter and tend to be spherical; can be formulated from inorganic materials (such as gold) or organic materials (such as polymers, lipids or peptides).

Orthogonality

Capacity of an engineered signalling platform to function independently of native or additional artificial pathways owing to having only minimal or no mutual, overlapping components.

Polyplexes

Drug delivery vehicles formed from cationic polymers with or without an additional hydrophilic block for complexing nucleic acids.

Prime editors

A genome-editing technology capable of changing DNA sequences without generating a double-stranded break; contains a Cas9 nickase fused to a reverse transcriptase that complexes with a prime editing gRNA complex to insert desired DNA sequences with site specificity; results in precise DNA modifications such as an insertion or deletion.

RNA interference

Inhibition of protein translation via binding or degrading messenger RNA.

Small interfering RNA

Short (19–22 base-pairs), double-stranded synthetic RNA that binds mRNA with high specificity and targets mRNA for degradation, resulting in inhibition of protein translation.

Solid-phase synthesis

A strategy for chemically synthesizing oligonucleotides in which nucleosides are immobilized on solid supports, and the strand is constructed one base at a time.

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DeJulius, C.R., Walton, B.L., Colazo, J.M. et al. Engineering approaches for RNA-based and cell-based osteoarthritis therapies. Nat Rev Rheumatol 20, 81–100 (2024). https://doi.org/10.1038/s41584-023-01067-4

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