A dual-engineered chondrocyte-targeting tetrahedral DNA-based nanoparticle for improved delivery of metformin and alleviation in osteoarthritis.

Abstract

Overcoming short intra-articular retention and poor chondrocyte uptake of drugs remains a major challenge for osteoarthritis (OA) therapy. Thereby, we developed a tetrahedral DNA (TDN)-based nano-delivery system (TLM@CAP) via a two-step engineering strategy, involving the introduction of tunable numbers of specific DNA loops to significantly enhance metformin loading capacity, and conjugation with a chondrocyte-affinity peptide (CAP) to confer chondrocyte-targeting capability. The TLM@CAP complex demonstrated improved chondrocyte uptake, prolonged joint retention exceeding 72 h, and deep cartilage penetration. In vivo, TLM@CAP outperformed free metformin in restoring mitochondrial function, reducing cellular senescence, and rebalancing extracellular matrix metabolism via AMPK/mTOR pathway activation in senescent chondrocytes. In an OA rat model, intra-articular TLM@CAP administration effectively alleviated pain, improved gait, and protected against cartilage and subchondral bone destruction. This work not only presents a potent targeted therapeutic strategy for OA but also advances the rational design of TDN-based nanoplatforms for drug delivery.