A cascade-release microsphere-engineered injectable hydrogel enables immune remodeling and sustained chondrogenesis...

Structural facial cartilage regeneration is impeded by limited intrinsic repair and injury-driven inflammatory remodeling, which promote fibrosis, matrix degradation, and phenotypic instability. Here, we report a temporally programmed immuno-chondrogenic hydrogel system that combines mesenchymal stem cells (MSCs) with cascade-release PLGA microspheres to build a pro-regenerative niche within facial cartilage defects. The injectable hydrogel showed a post-gelation modulus of ∼25 kPa, gelation within 15 s, and stable post-injection shape retention, enabling minimally invasive cell delivery, MSC retention, and defect-adaptive in situ molding. Bilayer porous PLGA microspheres were embedded within the hydrogel network to orchestrate staged biochemical cues. Cerium oxide nanozymes are massively released from the outer layer within the initial 20 days to eliminate reactive oxygen species and reshape the early inflammatory microenvironment, whereas the inner layer sustained TGF-β release for over 60 days to maintain chondrogenic stimulation during matrix formation. In vitro and in vivo studies showed that this system preserved MSC viability, promoted reparative M2 macrophage polarization, and enhanced cartilage-specific matrix deposition. Mechanistically, it suppressed inflammation-matrix degradation programs while activating the TGFBR1-SOX5 chondrogenic axis, thereby coupling immune remodeling with matrix homeostasis. In a rabbit auricular cartilage-associated model, the composite hydrogel preserved local architecture and promoted in situ maturation of cartilage-like tissue over 3 months. This hydrogel niche offers a minimally invasive and translatable material strategy for structural facial cartilage regeneration.