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 in vitro sustained/ROS-responsive release, thereby supporting localized delivery potential rather than proving WYRGRL-specific cartilage targeting. Moreover, the laser-responsive thermal behavior of K@BMT@HM provided a controllable local heating modality that may support thermosensitive in situ retention. Remarkably, the integrated K@BMT@HM, which couples the multi-component regulatory capacity of the K@BMT core with the multifunctional delivery advantages of the HM-SCHW carrier, was validated through a series of in vitro and in vivo experiments. Collectively, this work presents a rationally designed nanomedicine that integrates bioactive regulation with functionalized delivery to enhance chondroprotection, supporting further preclinical investigation of sustained and multimodal OA intervention. However, because the laser-assisted thermal component was validated only in a rat small-joint model, these findings cannot be directly extrapolated to human OA joints, where deeper articular cartilage and overlying skin, adipose tissue, synovium, and other tissues may substantially limit optical penetration and thermal delivery. In addition, because systematic single-component, two-component, and component-deletion controls were not performed, the present data should be interpreted as validating the integrated K@BMT@HM system as a whole rather than defining the quantitative contribution or indispensability of BDMC, MnTBAP, KRFK, 808-nm laser activation, the CS/SA hydrogel matrix, HA, or WYRGRL.