Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis

Nature Nanotechnology (2026)Cite this article

Subjects

Abstract

Intra-articular RNA therapeutics have shown promise in osteoarthritis (OA); however, maximizing their efficacy requires targeted delivery to degenerating cartilage within focal lesions. As OA progresses, cartilage degeneration worsens, necessitating disease-responsive targeting with enhanced delivery in advanced stages. Here we develop an anionic nanoparticle (NP) strategy for targeting glycosaminoglycan loss, a hallmark of OA’s progression that reduces cartilage’s negative charge. These NPs selectively diffuse and accumulate into matrix regions inversely correlated with glycosaminoglycan content owing to reduced electrostatic repulsion, a strategy we term ‘matrix inverse targeting’ (MINT). In a mouse model of OA, intra-articular delivery of luciferase messenger RNA-loaded MINT NPs demonstrated disease-severity-responsive expression. Using this strategy, we delivered ghrelin mRNA, as ghrelin has shown chondroprotection properties previously. Ghrelin mRNA-loaded MINT NPs reduced cartilage degeneration, subchondral bone thickening and nociceptive pain. Our findings highlight the potential of ghrelin mRNA delivery as a disease-modifying therapy for OA and the platform’s potential for lesion-targeted RNA delivery responsive to disease severity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MINT NPs harness electrostatic changes in OA lesions for precise targeting and enable disease-severity-responsive delivery and expression of Ghr mRNA.
Fig. 2: MINT NPs preferentially target OA-mimetic porcine cartilage and human OA cartilage, demonstrating superior penetration compared with cationic NPs.
Fig. 3: MINT NPs facilitate mRNA delivery in vitro, demonstrate potential for disease-severity-responsive targeting and exhibit biocompatibility.
Fig. 4: Fluc mRNA NPs exhibit diseases-severity-responsive luciferase expression in vivo.
Fig. 5: MINT NPs effectively deliver and express human Ghr mRNA in OA mice and attenuate OA progression.
Fig. 6: Ghr mRNA NPs reduce nociceptive pain associated with OA.

Similar content being viewed by others

Data availability

The main data that support the findings of this study are available in the paper and the Supplementary Information. Source/raw data will be available for research purposes from the corresponding authors upon reasonable request.

References

  1. Katz, J. N., Arant, K. R. & Loeser, R. F. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA 325, 568–578 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Jiang, P., Hu, K., Jin, L. & Luo, Z. A brief review of current treatment options for osteoarthritis including disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics. Ann. Med. Surg. 86, 4042–4048 (2024).

    Article  Google Scholar 

  3. Li, X., Shen, L., Deng, Z. & Huang, Z. New treatment for osteoarthritis: gene therapy. Precis. Clin. Med. 6, pbad014 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Evans, C. H., Ghivizzani, S. C. & Robbins, P. D. Osteoarthritis gene therapy in 2022. Curr. Opin. Rheumatol. 35, 37–43 (2023).

    Article  PubMed  Google Scholar 

  5. 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  PubMed  PubMed Central  CAS  Google Scholar 

  6. Nap, R. J. & Szleifer, I. Structure and interactions of aggrecans: statistical thermodynamic approach. Biophys. J. 95, 4570–4583 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bittersohl, B. et al. Delayed gadolinium-enhanced magnetic resonance imaging of hip joint cartilage: pearls and pitfalls. Orthop. Rev. 3, e11 (2011).

    Google Scholar 

  8. Tiderius, C. J., Olsson, L. E., Leander, P., Ekberg, O. & Dahlberg, L. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) in early knee osteoarthritis. Magn. Reson. Med. 49, 488–492 (2003).

    Article  PubMed  Google Scholar 

  9. Xiao, S., Tang, Y., Lin, Y., Lv, Z. & Chen, L. Tracking osteoarthritis progress through cationic nanoprobe-enhanced photoacoustic imaging of cartilage. Acta Biomater. 109, 153–162 (2020).

    Article  PubMed  CAS  Google Scholar 

  10. Chen, L. et al. Cationic poly-l-lysine-encapsulated melanin nanoparticles as efficient photoacoustic agents targeting to glycosaminoglycans for the early diagnosis of articular cartilage degeneration in osteoarthritis. Nanoscale 10, 13471–13484 (2018).

    Article  PubMed  CAS  Google Scholar 

  11. Lu, R. et al. Gadolinium-hyaluronic acid nanoparticles as an efficient and safe magnetic resonance imaging contrast agent for articular cartilage injury detection. Bioact. Mater. 5, 758–767 (2020).

    PubMed  PubMed Central  Google Scholar 

  12. Fazeli, P. K. et al. Treatment with a ghrelin agonist in outpatient women with anorexia nervosa: a randomized clinical trial. J. Clin. Psychiatry 79, 17m11585 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).

    Article  PubMed  CAS  Google Scholar 

  14. Guillory, B. et al. Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity. Aging Cell 16, 859–869 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Baatar, D., Patel, K. & Taub, D. D. The effects of ghrelin on inflammation and the immune system. Mol. Cell. Endocrinol. 340, 44–58 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Andrews, Z. B. et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Stoyanova, I. I. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders. Neurobiol. Dis. 72 Pt A, 72–83 (2014).

    Article  PubMed  CAS  Google Scholar 

  18. Sibilia, V. et al. Pharmacological characterization of the ghrelin receptor mediating its inhibitory action on inflammatory pain in rats. Amino Acids 43, 1751–1759 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sun, J. et al. Role and molecular mechanism of ghrelin in degenerative musculoskeletal disorders. J. Cell. Mol. Med. 27, 3681–3691 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Liu, J. et al. Ghrelin prevents articular cartilage matrix destruction in human chondrocytes. Biomed. Pharmacother. 98, 651–655 (2018).

    Article  PubMed  CAS  Google Scholar 

  21. Qu, R. et al. Ghrelin protects against osteoarthritis through interplay with Akt and NF-kappaB signaling pathways. FASEB J. 32, 1044–1058 (2018).

    Article  PubMed  CAS  Google Scholar 

  22. Bautista, C. A., Park, H. J., Mazur, C. M., Aaron, R. K. & Bilgen, B. Effects of chondroitinase ABC-mediated proteoglycan digestion on decellularization and recellularization of articular cartilage. PLoS ONE 11, e0158976 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bergholt, N. L., Lysdahl, H., Lind, M. & Foldager, C. B. A standardized method of applying toluidine blue metachromatic staining for assessment of chondrogenesis. Cartilage 10, 370–374 (2019).

    Article  PubMed  CAS  Google Scholar 

  24. Bajpayee, A. G. & Grodzinsky, A. J. Cartilage-targeting drug delivery: can electrostatic interactions help? Nat. Rev. Rheumatol. 13, 183–193 (2017).

    Article  PubMed  CAS  Google Scholar 

  25. Gao, T. et al. Non-destructive spatial mapping of glycosaminoglycan loss in native and degraded articular cartilage using confocal Raman microspectroscopy. Front. Bioeng. Biotechnol. 9, 744197 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pauli, C. et al. Comparison of cartilage histopathology assessment systems on human knee joints at all stages of osteoarthritis development. Osteoarthritis Cartilage 20, 476–485 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kleuskens, M. W. A., van Donkelaar, C. C., Kock, L. M., Janssen, R. P. A. & Ito, K. An ex vivo human osteochondral culture model. J. Orthop. Res. 39, 871–879 (2021).

    Article  PubMed  CAS  Google Scholar 

  28. Wei, Y. et al. Phospholipase A2 inhibitor-loaded micellar nanoparticles attenuate inflammation and mitigate osteoarthritis progression. Sci. Adv. 7, eabe6374 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Abumanhal-Masarweh, H. et al. Tailoring the lipid composition of nanoparticles modulates their cellular uptake and affects the viability of triple negative breast cancer cells. J. Control. Release 307, 331–341 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Uchimura, T. et al. Erythromycin acts through the ghrelin receptor to attenuate inflammatory responses in chondrocytes and maintain joint integrity. Biochem. Pharmacol. 165, 79–90 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Drevet, S., Favier, B., Brun, E., Gavazzi, G. & Lardy, B. Mouse models of osteoarthritis: a summary of models and outcomes assessment. Comp. Med. 72, 3–13 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Yu, L. et al. The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund’s adjuvant. Mol. Pain 4, 61 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  33. DeJulius, C. R. et al. Engineering approaches for RNA-based and cell-based osteoarthritis therapies. Nat. Rev. Rheumatol. 20, 81–100 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gao, J. et al. Gene therapy for CNS disorders: modalities, delivery and translational challenges. Nat. Rev. Neurosci. 25, 553–572 (2024).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Geiger, B. C., Wang, S., Padera, R. F. Jr., Grodzinsky, A. J. & Hammond, P. T. Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis. Sci. Transl. Med. 10, eaat8800 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Vedadghavami, A. et al. Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues. Acta Biomater. 93, 258–269 (2019).

    Article  PubMed  CAS  Google Scholar 

  41. Konttinen, Y. T. et al. Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis. Arthritis Rheum. 46, 953–960 (2002).

    Article  PubMed  CAS  Google Scholar 

  42. Paulini, F. et al. In vivo evaluation of DMSA-coated magnetic nanoparticle toxicity and biodistribution in rats: a long-term follow-up. Nanomaterials 12, 3513 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Dantas, G. P. F., Ferraz, F. S., Andrade, L. M. & Costa, G. M. J. Male reproductive toxicity of inorganic nanoparticles in rodent models: a systematic review. Chem. Biol. Interact. 363, 110023 (2022).

    Article  PubMed  CAS  Google Scholar 

  44. Li, Y., Vulpe, C., Lammers, T. & Pallares, R. M. Assessing inorganic nanoparticle toxicity through omics approaches. Nanoscale 16, 15928–15945 (2024).

    Article  PubMed  CAS  Google Scholar 

  45. Akalu, Y., Molla, M. D., Dessie, G. & Ayelign, B. Physiological effect of ghrelin on body systems. Int. J. Endocrinol. 2020, 1385138 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wakabayashi, H., Arai, H. & Inui, A. The regulatory approval of anamorelin for treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: facts and numbers. J. Cachexia Sarcopenia Muscle 12, 14–16 (2021).

    Article  PubMed  Google Scholar 

  47. Yasar, H. et al. Kinetics of mRNA delivery and protein translation in dendritic cells using lipid-coated PLGA nanoparticles. J. Nanobiotechnol. 16, 72 (2018).

    Article  Google Scholar 

  48. Lutz, J. et al. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. npj Vaccines 2, 29 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217, 345–351 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Qin, S. et al. mRNA-based therapeutics: powerful and versatile tools to combat diseases. Signal Transduct. Target. Ther. 7, 166 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Unti, M. J. & Jaffrey, S. R. Highly efficient cellular expression of circular mRNA enables prolonged protein expression. Cell Chem. Biol. 31, 163–176 e165 (2024).

    Article  PubMed  CAS  Google Scholar 

  52. Musumeci, G. et al. Histochemistry as a unique approach for investigating normal and osteoarthritic cartilage. Eur. J. Histochem. 58, 2371 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Zhang, L. et al. Self-assembled lipid–polymer hybrid nanoparticles: a robust drug delivery platform. ACS Nano 2, 1696–1702 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Xiao, Y. et al. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat. Commun. 13, 758 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Kong, N. et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci. Transl. Med. 11, eaaw1565 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Huang, X. et al. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat. Protoc. 17, 748–780 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Uchimura, T., Foote, A. T., Smith, E. L., Matzkin, E. G. & Zeng, L. Insulin-like growth factor II (IGF-II) inhibits IL-1beta-induced cartilage matrix loss and promotes cartilage integrity in experimental osteoarthritis. J. Cell. Biochem. 116, 2858–2869 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kawamoto, T. & Kawamoto, K. Preparation of thin frozen sections from nonfixed and undecalcified hard tissues using Kawamoto’s film method (2020). Methods Mol. Biol. 2230, 259–281 (2021).

    Article  PubMed  CAS  Google Scholar 

  59. Glasson, S. S., Blanchet, T. J. & Morris, E. A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061–1069 (2007).

    Article  PubMed  CAS  Google Scholar 

  60. Sleigh, J. N., Weir, G. A. & Schiavo, G. A simple, step-by-step dissection protocol for the rapid isolation of mouse dorsal root ganglia. BMC Res. Notes 9, 82 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63 (1994).

    Article  PubMed  CAS  Google Scholar 

  62. Kameda, T., Kaneuchi, Y., Sekiguchi, M. & Konno, S. I. Measurement of mechanical withdrawal thresholds and gait analysis using the CatWalk method in a nucleus pulposus-applied rodent model. J. Exp. Orthop. 4, 31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Kawamoto, T. & Kawamoto, K. Preparation of thin frozen sections from nonfixed and undecalcified hard tissues using Kawamot’s film method (2012). Methods Mol. Biol. 1130, 149–164 (2014).

    Article  PubMed  CAS  Google Scholar 

  64. McNulty, M. A. et al. A comprehensive histological assessment of osteoarthritis lesions in mice. Cartilage 2, 354–363 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Krenn, V. et al. Synovitis score: discrimination between chronic low-grade and high-grade synovitis. Histopathology 49, 358–364 (2006).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from Ellison Foundation (to L.Z. and N.J.), Prime Minister Research Fellowship (PMRF) (to M.D.), NIH grant 1R01AR077718 (to N.J.), 1R01AR077146-01A1 (L.Z.) and 1R21AR085398-01 (to L.Z. and N.J.). The work of S. Lee was supported by the Nano and Material Technology Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (RS-2024-00405574). S.D.K. acknowledges the support received by the ‘Khorana Program for Scholars’ awarded by the Indo-US Science and Technology Forum (IUSSTF). We utilized ChatGPT (OpenAI) to aid in language refinement and improve the clarity and cohesiveness of this paper. All intellectual content, scientific interpretations and conclusions remain the sole responsibility of the authors.

Author information

Author notes

  1. Jingjing Gao

    Present address: Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA

  2. These authors contributed equally: Mahima Dewani, Anjali Rajesh Mamidwar.

  3. These authors jointly supervised this work: Nitin Joshi, Li Zeng.

Authors and Affiliations

  1. Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Mahima Dewani, Nutan Bhingaradiya, Nishkal Pisal, Arpita Banerjee, Christopher Jiang, Aashman Gupta, Shrihari D. Katti, Ziting Xia, Joshua Karp, Sohyung Lee, Jeffrey M. Karp, Jingjing Gao & Nitin Joshi

  2. Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India

    Mahima Dewani & Arpita Banerjee

  3. Harvard Medical School, Boston, MA, USA

    Mahima Dewani, Nutan Bhingaradiya, Sohyung Lee, Jeffrey M. Karp, Jingjing Gao & Nitin Joshi

  4. Department of Immunology, Tufts University School of Medicine, Boston, MA, USA

    Anjali Rajesh Mamidwar, Miraj Rawal, Jingshu Liu, Sihan Liu, Elyse Blank, Keren Chen, Amirtaa Nedumaran & Li Zeng

  5. Graduate Program in Biomedical Research (MBR), Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA

    Anjali Rajesh Mamidwar & Amirtaa Nedumaran

  6. Program in Genetics, Molecular and Cellular Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA

    Jingshu Liu & Li Zeng

  7. Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY, USA

    Dongsung Park

  8. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jeffrey M. Karp

  9. Broad Institute, Cambridge, MA, USA

    Jeffrey M. Karp

  10. Harvard Stem Cell Institute, Cambridge, MA, USA

    Jeffrey M. Karp

  11. Program of Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA

    Li Zeng

  12. Department of Orthopaedics, Tufts Medicine, Boston, MA, USA

    Li Zeng

Authors
  1. Mahima Dewani
    View author publications

    Search author on:PubMed Google Scholar

  2. Anjali Rajesh Mamidwar
    View author publications

    Search author on:PubMed Google Scholar

  3. Miraj Rawal
    View author publications

    Search author on:PubMed Google Scholar

  4. Nutan Bhingaradiya
    View author publications

    Search author on:PubMed Google Scholar

  5. Jingshu Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Nishkal Pisal
    View author publications

    Search author on:PubMed Google Scholar

  7. Sihan Liu
    View author publications

    Search author on:PubMed Google Scholar

  8. Elyse Blank
    View author publications

    Search author on:PubMed Google Scholar

  9. Arpita Banerjee
    View author publications

    Search author on:PubMed Google Scholar

  10. Dongsung Park
    View author publications

    Search author on:PubMed Google Scholar

  11. Christopher Jiang
    View author publications

    Search author on:PubMed Google Scholar

  12. Aashman Gupta
    View author publications

    Search author on:PubMed Google Scholar

  13. Shrihari D. Katti
    View author publications

    Search author on:PubMed Google Scholar

  14. Keren Chen
    View author publications

    Search author on:PubMed Google Scholar

  15. Ziting Xia
    View author publications

    Search author on:PubMed Google Scholar

  16. Amirtaa Nedumaran
    View author publications

    Search author on:PubMed Google Scholar

  17. Joshua Karp
    View author publications

    Search author on:PubMed Google Scholar

  18. Sohyung Lee
    View author publications

    Search author on:PubMed Google Scholar

  19. Jeffrey M. Karp
    View author publications

    Search author on:PubMed Google Scholar

  20. Jingjing Gao
    View author publications

    Search author on:PubMed Google Scholar

  21. Nitin Joshi
    View author publications

    Search author on:PubMed Google Scholar

  22. Li Zeng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

M.D., A.R.M., J.G., L.Z. and N.J. conceived and designed the project. M.D., A.R.M., M.R., N.B., S. Liu, J.L., J.G., N.P., E.B., A.B., C.J., A.G., S.D.K., K.C., A.N., J.K. and Z.X. performed the experiments and analysed the data. D.P. conducted and analysed the molecular docking simulation studies. M.D., A.R.M., N.J. and L.Z. wrote the paper. J.G., S. Lee and J.M.K. edited the paper. N.J. and L.Z. supervised the overall research. All authors discussed the results and commented on the paper.

Corresponding authors

Correspondence to Jingjing Gao, Nitin Joshi or Li Zeng.

Ethics declarations

Competing interests

N.J., J.M.K., L.Z., M.D., J.G. and A.R.M. have one pending patent (US patent application number 63/756,779) based on the nanoparticle technology described in this work. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Christopher Evans and Fergal O’Brien for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Methods, Tables 1 and 2, Figs. 1–7 and sequence of ghrelin mRNA.

Reporting Summary

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dewani, M., Mamidwar, A.R., Rawal, M. et al. A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis. Nat. Nanotechnol. (2026). https://doi.org/10.1038/s41565-025-02101-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41565-025-02101-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research