A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis PMID: 41535382

ADC Targets in Oncology

2026-04-10

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

Nat Nanotechnol. 2026 Jan 14. doi: 10.1038/s41565-025-02101-0.

Mahima Dewani ^# ¹ ² ³ , Anjali Rajesh Mamidwar ^# ⁴ ⁵ , Miraj Rawal ⁴ , Nutan Bhingaradiya ¹ ³ , Jingshu Liu ⁴ ⁶ , Nishkal Pisal ¹ , Sihan Liu ⁴ , Elyse Blank ⁴ , Arpita Banerjee ¹ ² , Dongsung Park ⁷ , Christopher Jiang ¹ , Aashman Gupta ¹ , Shrihari D Katti ¹ , Keren Chen ⁴ , Ziting Xia ¹ , Amirtaa Nedumaran ⁴ ⁵ , Joshua Karp ¹ , Sohyung Lee ¹ ³ , Jeffrey M Karp ¹ ³ ⁸ ⁹ ¹⁰ , Jingjing Gao ¹¹ ¹² ¹³ , Nitin Joshi ¹⁴ ¹⁵ , Li Zeng ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
2. Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
3. Harvard Medical School, Boston, MA, USA.
4. Department of Immunology, Tufts University School of Medicine, Boston, MA, USA.
5. Graduate Program in Biomedical Research (MBR), Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
6. Program in Genetics, Molecular and Cellular Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA.
7. Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY, USA.
8. Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
9. Broad Institute, Cambridge, MA, USA.
10. Harvard Stem Cell Institute, Cambridge, MA, USA.
11. Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
12. Harvard Medical School, Boston, MA, USA. [email protected].
13. Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA. [email protected].
14. Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
15. Harvard Medical School, Boston, MA, USA. [email protected].
16. Department of Immunology, Tufts University School of Medicine, Boston, MA, USA. [email protected].
17. Program in Genetics, Molecular and Cellular Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. [email protected].
18. Program of Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. [email protected].
19. Department of Orthopaedics, Tufts Medicine, Boston, MA, USA. [email protected].
# Contributed equally.

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.