pH‐Responsive Engineered Exosomes Enhance Endogenous Hyaluronan Production by Reprogramming Chondrocytes for Cartilage Repair

Abstract Trauma or inflammation‐caused cartilage injury leads to joint dysfunction and pain. Exogenous hyaluronic acid (HA) injection is a well‐established treatment, but it has a short duration in vivo and requires multiple injections. Here, a new strategy for in situ reprogramming chondrocytes to continuously produce endogenous high molecular weight HA is developed. This involves a pH‐responsive engineered exosome decorated with vesicular stomatitis virus glycoprotein (VSV‐G) and hyaluronan synthase type 2 (HAS2). Such engineered exosomes successfully deliver HAS2 to the chondrocyte membranes via VSV‐G‐mediated membrane fusion triggered by low pH, rather than being degraded in lysosomes. This results in the generation of HAS2‐chondrocytes, which are characterized to produce high molecular weight HA in vitro and in vivo. With increased endogenous HA, the injected engineered exosomes enhance cartilage regeneration and inhibit osteoarthritis (OA) progression. Notably, one‐shot administration of engineered exosomes drastically increases the intra‐articular concentration of high molecular weight HA to 145% of the exogenous HA injection group. Importantly, such endogenous HA is sustained for 4 weeks, whereas the injected exogenous HA rapidly decreases within 2 weeks. The findings demonstrate that pH‐responsive engineered exosomes capable of generating endogenous HA hold great potential to replace the treatment of multiple injections of exogenous HA for cartilage repair.