Programmable hydrogel-nanocapsule protein delivery system targeting dense cartilage regeneration for osteoarthritis therapy

The clinical translation of protein therapeutics for osteoarthritis has been hampered by rapid synovial clearance, poor penetration into cartilage, and insufficient retention under joint loading. In this work, we develop hydro/nano-bFGF, a programmable system that integrates an FGF-loaded nanocapsule (nano-bFGF) with an injectable, cartilage-adhesive hydrogel. Nano-bFGF is generated through interfacial polymerization of monomers with enzyme-cleavable crosslinkers directly on the protein surface, forming a nanoscale shell that preserves bioactivity while enabling pathology-specific disassembly. The hydrogel anchors nano-bFGF to the cartilage surface and undergoes gradual degradation in response to disease-associated enzymatic activity, allowing spatiotemporally programmed release aligned with the joint microenvironment. This spatiotemporally controlled design enhances intra-cartilage transport, prolongs local retention, and maintains growth factor functionality. In human osteoarthritic cartilage explants, nano-bFGF doubles glycosaminoglycan deposition and triples type II collagen expression. In a rat model, hydro/nano-bFGF restores cartilage integrity, preserves subchondral bone architecture, and achieves restoration of cartilage thickness. Owing to its modular design, this strategy is broadly adaptable to diverse protein therapeutics and degenerative joint diseases, offering a generalizable platform for spatiotemporally precise biologic delivery. In osteoarthritis, protein therapeutics show poor joint retention and cartilage penetration. Here, authors develop a programmable two-stage, enzyme-responsive hydrogel-nanocapsule system to deliver a model protein drug and promote cartilage regeneration.