Chondrocyte-targeting TDN nanoparticle (TLM@CAP) delivers metformin, alleviates rat OA pain and protects cartilage.

Effective treatment for osteoarthritis (OA) faces significant hurdles, primarily due to the avascular nature of cartilage, which impedes drug penetration and retention within the joint. Current intra-articular injections often suffer from short residence times and poor chondrocyte uptake, limiting therapeutic efficacy. Metformin, a widely used antidiabetic drug, has shown promise in OA due to its AMPK/mTOR pathway modulating effects on chondrocyte metabolism and senescence, but its systemic delivery has off-target effects, and local delivery struggles with the aforementioned challenges. This research addresses the critical need for targeted and sustained drug delivery systems to enhance metformin's therapeutic potential in OA.

Researchers developed a novel tetrahedral DNA (TDN)-based nano-delivery system, TLM@CAP, designed for improved metformin delivery to chondrocytes. This system was engineered in two steps: first, by introducing tunable DNA loops to significantly enhance metformin loading capacity, and second, by conjugating it with a chondrocyte-affinity peptide (CAP) to confer specific chondrocyte-targeting. The team evaluated TLM@CAP's performance in vitro for chondrocyte uptake and in vivo for joint retention and cartilage penetration. The therapeutic efficacy was then assessed in an OA rat model via intra-articular administration, comparing TLM@CAP against free metformin on pain, gait, and cartilage/subchondral bone integrity.

The dual-engineered TLM@CAP complex demonstrated significantly improved chondrocyte uptake and prolonged joint retention, exceeding 72 hours, along with deep cartilage penetration. In vivo, TLM@CAP markedly outperformed free metformin in several key areas. It effectively restored mitochondrial function, reduced cellular senescence, and rebalanced extracellular matrix metabolism in senescent chondrocytes, primarily through the activation of the AMPK/mTOR pathway. In the OA rat model, intra-articular administration of TLM@CAP led to substantial therapeutic benefits:

TLM@CAP administration effectively alleviated pain, improved gait, and protected against cartilage and subchondral bone destruction. These findings highlight the system's ability to overcome conventional drug delivery limitations and provide superior therapeutic outcomes.