Sustained and bioactive BMP-2 delivery via nanoconfinement-affinity coupled silk fibroin microparticles for enhanced bone regeneration.

Achieving sustained and bioactive drug delivery remains a formidable challenge in regenerative medicine, primarily due to the inherent instability and rapid clearance kinetics of therapeutic agents. Here, we report a biomimetic delivery platform based on nanoporous biomineralized silk fibroin microparticles, engineered through a unified in situ biomineralization and critical-point drying process. This architecture employs a coupled nanoconfinement-affinity strategy: the interconnected nanofibrous network imposes physical confinement, while the deposited hydroxyapatite coating provides strong affinity for molecular retention via non-covalent interactions. By leveraging these biologically benign interactions, the platform avoids harsh chemical modifications and maximizes the preservation of therapeutic bioactivity. We demonstrate the exceptional versatility of this platform by achieving the extended release of diverse therapeutic agents ranging from small molecules and nucleic acids to proteins over a five-week period. Using bone morphogenetic protein-2 (BMP-2) as a model therapeutic, the platform enables sustained and bioactive delivery for over 8 weeks, facilitating the complete bridging of critical-sized bone defects in vivo. In summary, we present a coupled nanoconfinement-affinity platform that ensures prolonged and bioactive therapeutic availability, offering a versatile strategy for the repair of challenging bone defects.