Bajpayee Receives $3.1M NIH Grant to Develop Cartilage-Targeted Gene Therapy for Osteoarthritis
Portrait of Ambika Goel Bajpayee. Photo by Alyssa Stone/Northeastern University.
Ambika Goel Bajpayee, Professor of Bioengineering at Northeastern University, has received a five-year, $3.1 million R01 grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, to develop a nonviral, cartilage-targeted gene therapy for osteoarthritis (OA).
A major barrier to developing effective OA therapies is delivering drugs and gene therapies into cartilage, a dense, avascular tissue that is exceptionally difficult to penetrate. Bajpayee’s laboratory has pioneered charge-based drug delivery approaches that exploit the high negative fixed-charge density of cartilage to rapidly transport and retain therapeutics throughout the tissue. This new NIH-funded work extends that strategy to gene therapy using charge-reversed exosomes—naturally derived extracellular vesicles engineered with a positive surface charge that enables them to penetrate through the full thickness of cartilage and deliver genetic cargo directly to chondrocytes.
The project will develop these exosomes as a nonviral platform for intra-articular gene delivery, with the goal of achieving sustained therapeutic effects following a single injection. The team will investigate delivery of genetic cargo designed to simultaneously suppress inflammation and cartilage degeneration while targeting molecular pathways associated with OA pain. By addressing both structural disease progression and pain, which is the primary reason patients seek treatment, the work aims to overcome key barriers that have limited the clinical translation of disease-modifying therapies for OA. Rachel Miller, Professor at Rush University Medical Center in Chicago and an expert in osteoarthritis pain, is a co-principal investigator on the project and will lead studies evaluating pain-related outcomes.
Bajpayee is a recipient of the 2025 Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the U.S. government on outstanding scientists and engineers. She was nominated for the award by the National Institutes of Health.
The project runs from June 2026 through May 2031.
Related articles: Small Methods Journal | Osteoarthritis and Cartilage Journal | NanoToday
Abstract Source: NIH
Project Summary Gene therapy has the potential to facilitate targeted expression of therapeutic proteins to promote cartilage regeneration in osteoarthritis (OA). The dense, avascular, aggrecan-glycosaminoglycan rich negatively charged cartilage, however, hinders their transport to reach chondrocytes in effective doses. While viral vector mediated gene delivery has shown promise, concerns over immunogenicity and tumorigenic side-effects persist. To address this, we have developed surface-modified cartilage-targeting MSC exosomes as non-viral carriers for gene therapy. MSC derived exosomes have intrinsic therapeutic potential as they can induce cartilage repair and are non-immunogenic, making them desirable for gene delivery. We have engineered charge-reversed cationic exosomes by anchoring cartilage targeting optimally charged arginine-rich cationic peptide (CPC) motifs into the anionic exosome bilayer (Exo-CPC) by using buffer pH as a charge-reversal switch. Exo-CPC use charge interactions to penetrate through the full thickness of arthritic cartilage (close to tidemark) and deliver the packaged genetic material cargo to chondrocytes residing in the deep tissue layers while native anionic exosomes cannot. They can also bind within the synovial joint, making them effective for OA pain relief gene therapy. Here we will engineer charge-reversed Exo-CPC for delivery of IL-1RA (receptor antagonist of interleukin-1) mRNA and NaV1.8 (voltage gated sodium channel 1.8) inhibitor siRNA to stimulate both disease modifying response and long-term pain relief with a one-time intra-articular dose. IL-1RA mRNA targets are in the chondrocytes and synovium cells; Nav1.8 expressing nerves innervate into synovium and subchondral bone in OA – sites that Exo-CPC can readily target. Aim 1 will engineer cartilage targeting Exo-CPC for delivery of IL- 1RA mRNA and Nav1.8 inhibitor siRNA. Their ability to deliver IL-1RA mRNA to chondrocytes and IL-1RA protein translation efficiency will be evaluated in-vitro. Exo-CPC-Na v1.8’s ability to reduce NaV1.8 bioactivity of sensory nerves will also be evaluated. In Aim 2, their distribution intra-articular (proximity to NaV1.8-positive nerves), extra-articular, and DRG and spinal cord using partial meniscectomy NaV1.8-tdTomato reporter mice OA models will be evaluated. Additionally, their dose dependent reduction on MMP activity, neuronal excitability and pain- related behaviors, and any immunogenicity will be assessed. Aim 3 will use the determined functional doses to study the long-term disease modifying and pain-relief effects of mono and combination therapy with Exo-CPC- IL-1RA and Exo-CPC-Nav1.8 in rescuing injury induced tissue structural damage as well as in reducing pain (weight bearing asymmetry) for up to one month following IA administration in early vs. late stages (intervention at 2 vs 6 weeks) of MMT (medial meniscectomy) induced OA rats. The project paves way for utilizing the intrinsic therapeutic potential of MSC Exosomes as viral-free, non-immunogenic carriers for OA gene therapy by employing cartilage as a drug depot. Cationic exosomes can be used to deliver other OA gene targets, and can be widely used for targeting other negatively charged tissues like meniscus, ligaments, discs, fracture callus etc.