Activating macrophage-mediated efferocytosis via cascade-responsive nanoplatform for improved osseointegration of implant in diabetes

A smart-responsive implant coating was developed to regulate innate immunity for enhanced bone regeneration in diabetes. • Phenylboronic ester bonds link the titanium platform with drug-loaded particles, enabling smart-triggered drug release. • Hyaluronic acid-based microparticles (HPP@Cur) ensure precise delivery and improve the state of injured macrophages. • The immune microenvironment is effectively reshaped, actively guiding biomineralization and bone regeneration. Diabetes mellitus (DM) creates a chronic inflammatory microenvironment that severely compromises osseointegration, the key to implant success. This impairment is largely driven by hyperglycemia-induced metabolic disturbances, which trigger oxidative stress and mitochondrial dysfunction in immune cells. Efferocytosis, the macrophage-mediated clearance of apoptotic cells, is a crucial self-resolving anti-inflammatory process. Herein, we developed a smart drug-delivery system on the surface of titanium (Ti) implant for reactivating macrophage function by promoting efferocytosis. Hyaluronic acid (HA) grafted with phenylboronic acid (PBA), poly- l -lysine (PLL) and curcumin (Cur) were assembled into HPP NPs (HA-PBA-PLL nanoparticles). The NPs were anchored to a polydopamine-coated Ti implant via reversible PBA ester linkages. Upon implantation into a diabetic bone defect with high ROS levels, these linkages underwent rapid cleavage, triggering the on-demand release of NPs. Following release, HA-mediated CD44 receptor recognition enabled preferential macrophage targeting and cellular uptake. Subsequent exposure to the acidic environment of the endosome/lysosome induced NPs degradation and Cur release. This targeted delivery would synergistically enhance efferocytosis, thereby reprogramming macrophages, restoring immune homeostasis, and ultimately promoting osseointegration in a diabetic microenvironment. This approach offers a novel therapeutic strategy for resetting immune function and breaking the chronic inflammatory cycle to improve osseointegration of the implant in DM.