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Published on: July 26, 2017
A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis
Mahima Dewani1,2,3, Anjali Rajesh Mamidwar4,5, Miraj Rawal4
1Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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.
Insights
Anionic nanoparticles target osteoarthritis cartilage by exploiting glycosaminoglycan loss. This matrix inverse targeting (MINT) strategy delivers therapeutic RNA, reducing degeneration and pain in OA models.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Nanotechnology
Background:
- Osteoarthritis (OA) necessitates targeted intra-articular RNA therapeutics for cartilage repair.
- Current OA treatments lack disease-severity-responsive targeting for advanced lesions.
- Glycosaminoglycan (GAG) loss is a key indicator of OA progression, reducing cartilage's negative charge.
Purpose of the Study:
- To develop an anionic nanoparticle (NP) strategy for disease-severity-responsive, targeted RNA delivery in osteoarthritis.
- To investigate the efficacy of 'matrix inverse targeting' (MINT) for concentrating NPs in GAG-deficient cartilage regions.
- To evaluate the therapeutic potential of ghrelin mRNA delivered via MINT NPs for OA treatment.
Main Methods:
- Anionic nanoparticles (NPs) were designed to target GAG-depleted cartilage regions via electrostatic interactions.
- The MINT strategy leverages reduced electrostatic repulsion in GAG-loss areas for NP accumulation.
- Luciferase mRNA and ghrelin mRNA were loaded into MINT NPs for intra-articular delivery in a mouse OA model.
Main Results:
- MINT NPs demonstrated disease-severity-responsive accumulation in degenerating cartilage.
- Intra-articular delivery of luciferase mRNA-loaded MINT NPs showed targeted expression correlating with OA severity.
- Ghrelin mRNA-loaded MINT NPs significantly reduced cartilage degeneration, subchondral bone thickening, and nociceptive pain.
Conclusions:
- The MINT strategy enables targeted RNA delivery to OA cartilage lesions, responsive to disease severity.
- Ghrelin mRNA delivery via MINT NPs shows potential as a disease-modifying therapy for osteoarthritis.
- This NP platform offers a promising approach for lesion-specific RNA therapeutics in OA.
