Pathological progression features-guided biphasic drug delivery supramolecular hydrogel for synergistic cartilage protection in osteoarthritis

Osteoarthritis (OA) remains a major clinical challenge due to its complex pathogenesis and the current lack of effective therapies capable of halting the progressive degradation of cartilage. Our bioinformatics analysis reveals that synovial inflammation precedes cartilage degeneration in early-stage OA, and chondrocyte pyroptosis present in both early and late stages, further promoting cartilage degeneration. Based on these findings, we developed a novel pathological progression-guided biphasic drug delivery supramolecular hydrogel (SP Gel/DS@cLip) featured by dual cross-linking where both spermidine (SP) and disulfiram (DS)-loaded cationic liposomes (DS@cLip) actively participate in hydrogel network formation. SP Gel/DS@cLip demonstrated favorable injectability, self-healing capacity, lubrication performance and biocompatibility. Notably, the hydrogel system enables rapid SP release to target early synovial inflammation and sustained DS release to inhibit chondrocyte pyroptosis, exerting significant cartilage protective effects both in vitro and in vivo . This pathological progression features-guided biphasic drug delivery system offers a promising therapeutic approach with strong potential for clinical translation in OA treatment. A pathological progression-guided biphasic supramolecular hydrogel (SP Gel/DS@cLip) achieves early synovial anti-inflammation and sustained chondrocyte anti-pyroptosis, synergistically halting osteoarthritis progression via sequential drug release.