Ultralong-Acting PLGA Microspheres Engineered to Sustain Release across the Entire Bone-Regeneration Timeline

Bone defect repair is a precisely choreographed, multiphase cascade that imposes temporally distinct demands on the implanted scaffold. The critical challenge is to create an implant that sustains potent anti-inflammatory and osteogenic signals while eroding at a pace matched to the more than 6-month remodeling timeline. Here, we reported ultralong-acting microspheres that meet this requirement across the entire regeneration program. By synergistically integrating polydopamine-coated poly(lactic-co-glycolic acid) (PLGA–PDA) microspheres with nanohydroxyapatite (nHAP) and mesenchymal stem cell-derived exosomes (Exo), the nHAP/PLGA–PDA@Exo system reconciled extended degradation with durable bioactivity. nHAP neutralized acidic PLGA byproducts to decelerate matrix erosion and release calcium ions, amplifing osteoinduction. Exo modulated inflammation, promoted angiogenesis, and enhanced tissue regeneration, while the PDA coating maximized Exo loading and orchestrated its sustained release. The microspheres released bioactive Exo for more than 3 weeks and retained mechanical integrity for over 6 weeks, thereby furnishing continuous immunomodulation, robust osteogenesis, and time-matched structural support. By dynamically coordinating immune modulation and bone formation throughout the inflammatory, reparative, and remodeling phases, nHAP/PLGA–PDA@Exo offered a clinically translatable strategy for bone defects.