Multiregulatory hydrogel supramolecular nanomedicine for reprogramming cartilage homeostasis in osteoarthritis.

Osteoarthritis (OA) is a multifactorial degenerative joint disorder characterized by intricate interactions among oxidative stress, inflammation, apoptosis, and extracellular matrix (ECM) degradation, ultimately disrupting chondrocyte homeostasis and accelerating cartilage deterioration. Although advanced intra-articular biomaterial systems have improved local therapeutic delivery for OA, the rational integration of a multi-component bioactive core with a multifunctional carrier remains challenging. In this study, a multifunctional nanomedicine, K@BMT@HM, was developed by integrating a supramolecular bioactive core with a functionalized hydrogel microsphere carrier. The K@BMT core, composed of the KRFK peptide, bisdemethoxycurcumin (BDMC), and MnTBAP, exerted multi-dimensional regulatory effects by enhancing antioxidant defense, restoring autophagic flux, and modulating TGF-β-associated signaling, thereby mitigating oxidative stress, inflammation, and apoptosis while favoring ECM anabolic balance in chondrocyte-based assays. However, because TGF-β signaling is highly context- and compartment-dependent, these observations should not be interpreted as evidence that TGF-β activation is uniformly beneficial across the whole joint. Meanwhile, the HM-SCHW carrier, composed of chitosan (CS), sodium alginate (SA), hyaluronic acid (HA), and WYRGRL peptide, provided thermosensitive depot formation, lubrication, cartilage-associated localization/retention, and