2. Academic Validation
  3. A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis

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

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.
PMID: 41535382 DOI: 10.1038/s41565-025-02101-0
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.

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