Multifunctional bone repair platform: Cytokines scavenging and sequential drug release for osteoporotic bone defects

• Macrophage membrane-liposomes nanovesicles embedded in GelMA to form GelMA/MM-Lipo hydrogel. • Membrane receptors scavenged RANKL/TNF-α/IL-6, rebalancing osteoclast-osteoblast. • Sequential release: hydrogel liberated MM-Lipo, then sustained PTH 1–34. • GelMA/MM-Lipo@PTH promoted bone formation and reduced bone absorption in OBD mice. The repair of osteoporotic bone defect (OBD) continues to be challenged by the persistent inflammatory imbalance and impaired osteogenesis. Inspired by the immunomodulatory role of macrophages, we developed a multifunctional bone repair platform consisting of macrophage membrane-liposome hybrid nanovesicles (MM-Lipo) embedded in the GelMA hydrogel. The MM-Lipo nanovesicles, which present membrane-anchored cytokine receptors, effectively scavenged excess RANKL, TNF-α, IL-6 at the defect sites, thereby regulating the local microenvironment. The aqueous core of the nanovesicles allowed for the encapsulation of the hydrophilic teriparatide (PTH 1–34). The GelMA hydrogel served as a sustained-release reservoir, facilitating the sequential delivery of both nanovesicles and drug to promote osteogenic differentiation. In vitro , MM-Lipo efficiently depleted cytokines, inhibited RANKL-induced osteoclastogenesis, and reversed the inhibitory effects TNF-α on osteoblast function. The teriparatide-loaded formulation (MM-Lipo@PTH) further upregulated the expression of osteogenic markers (OSX, OCN) and promoted mineralized matrix deposition. In the mouse OBD model, a single implantation of the GelMA/MM-Lipo@PTH hydrogel rebalanced osteoclast and osteoblast activity, accelerated bone regeneration, and supported well-organized collagen architecture. This synergistic strategy integrates the cytokines-scavenging capability of biomimetic membrane with the controlled, sequential release properties of hydrogel, offering a promising therapeutic platform for inflammation-associated metabolic bone disorders. Abbreviations: ALP, Alkaline phosphatase; ALT, Alanine Aminotransferase; AST, Aspartate aminotransferase; BCA, Bicinchoninic acid; BCIP/NBT, 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium; BMSC, bone mesenchymal stem cells; BUN, Blood urea nitrogen; CCK-8, Cell counting kit-8; CREA, Creatinine; DAPI, 4′,6-diamidino-2-phenylindole; Dil, 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocar bocyanine Perchlorate; DiO, 3,3′-Dioctadecyloxacar bocyanine perchlorate; ECL, Enhanced chemiluminescence; EDTA, Ethylenediaminetetraacetic acid; ELISA, Enzyme-linked immunosorbent assay; FBS, Fetal bovine serum; FRET, Förster resonance energy transfer; GelMA, Gelatin methacryloyl; H&E, hematoxylin and eosin; IL-6, Interleukin-6; LAP, Lithium phenyl-2,4,6-trimethylbenzoylphosphinate; α-MEM, α-minimum essential medium; OCN, Osteocalcin; OSX, Osterix; PBS, Phosphate buffered saline; PVDF, Polyvinylidene fluoride; RANKL, Receptor activator of nuclear factor-κ B ligand; SDS-PAGE, Sodium dodecyl sulfate–polyacrylamide gel electrophoresis; TBST, Tris-buffered saline with tween-20; TNF-α, Tumor necrosis factor α; TRAP, Tartrate-resistant acid phosphatase; TRITC, Tetramethylrhodamine isothiocyanate.