Improved tendon repair with optimized chemically modified mRNAs: Combined delivery of Pdgf-BB and IL-1Ra using...

Tendon injuries, common in both athletic and non-athletic populations, present significant challenges due to their slow healing and the formation of scar tissue, which impairs function and potentially increases the risk of (re-)rupture. Conventional treatments often yield suboptimal functional and structural repair. This study investigates the potential of mRNA-based therapeutics to enhance tendon healing by targeting 2 distinct pathways via the delivery of chemically modified ARCA-capped mRNAs (cmRNAs) encoding Interleukin-1 receptor antagonist (IL1RA) and Platelet-Derived Growth Factor-BB (PDGF-BB) using injectable nanoparticle (NP) carriers. In vitro experiments demonstrate successful cmRNA delivery and translation, resulting in increased tendon cell proliferation, migration, and anti-inflammatory responses. In vivo, cmRNA treatment notably enhances tendon repair in a rat patellar tendon defect model, by reducing pro-inflammatory cytokines and fibrotic markers while enhancing repair tissue structure. These findings suggest that NP-based cmRNA delivery represents a promising therapeutic strategy for improving tendon healing, offering better outcomes over existing treatments by targeting both inflammatory and regenerative pathways. STATEMENT OF SIGNIFICANCE: In this study, we investigate an mRNA-based therapeutic approach aimed at enhancing tendon healing in a small animal model. Utilizing bioreducible poly(amidoamine)-based polymeric nanoparticles (PAA PNPs) for the delivery of cmRNAs encoding Interleukin-1 receptor antagonist (IL1RA) and Platelet-Derived Growth Factor-BB (PDGF-BB), we demonstrate effective delivery and protein translation in vitro and ex vivo, resulting in enhanced tendon cell proliferation, migration, and robust anti-inflammatory responses. By combining these therapeutic cmRNAs, we show improved tendon repair in vivo, with accelerated tissue regeneration, better collagen fiber organization, and signs of reduced fibrotic scarring. These findings highlight the potential of nanoparticle-mediated cmRNA delivery targeting two distinct pathways to improve tendon healing, offering a promising alternative to current treatments that often yield suboptimal results.