Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2026年1月14日

查看全文
  • Mahima Dewani,
  • Anjali Rajesh Mamidwar,
  • Miraj Rawal,
  • Nutan Bhingaradiya,
  • Jingshu Liu,
  • Nishkal Pisal,
  • Sihan Liu,
  • Elyse Blank,
  • Arpita Banerjee,
  • Dongsung Park,
  • Christopher Jiang,
  • Aashman Gupta,
  • Shrihari D. Katti,
  • Keren Chen,
  • Ziting Xia,
  • Amirtaa Nedumaran,
  • Joshua Karp,
  • Sohyung Lee,
  • Jeffrey M. Karp,
  • Jingjing Gao,
  • Nitin Joshi,
  • Li Zeng

摘要

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.