Modular hydrogel niche orchestrates microenvironment detoxification and stem cell redirecting toward precision osteoarthritis therapy.

Osteoarthritis (OA), a debilitating degenerative joint disease driven by chronic inflammation and cartilage degradation, remains inadequately addressed by current therapies. While mesenchymal stem cells (MSCs) offer regenerative potential, their clinical efficacy is hindered by poor survival, transient retention, and pathological joint microenvironments. Here, we present a bioengineered hydrogel-based stem cell niche (PPT hydrogel) that dynamically coordinates microenvironmental reprogramming and MSC functional redirection to achieve sustained OA treatment. The PPT platform integrates intrinsic antioxidative and anti-inflammatory properties to neutralize OA-associated oxidative stress and inflammation while enhancing bone marrow MSCs (BMSCs) survival via Hedgehog signaling activation, overcoming limitations of conventional cell delivery. By incorporating a pro-differentiation agent, PPT hydrogel steers BMSCs toward stable hyaline cartilage regeneration, suppressing the formation of fibrotic and hypertrophic cartilage even under inflammatory conditions. Furthermore, PPT amplifies BMSCs paracrine signaling to restore redox homeostasis and autophagy flux in resident chondrocytes through FOXO1-dependent mechanisms, establishing a self-reinforcing therapeutic loop. The modular amphiphilic design enables spatiotemporal co-delivery of diverse therapeutics, synergistically regulating stem cell behavior and host tissue responses. Through bridging stem cell-chondrocyte crosstalk, this multifaceted PPT hydrogel represents a transformative paradigm for precision regenerative medicine, offering a universally adaptable platform to address complex inflammatory and degenerative diseases beyond OA.