ModernizingTraditional Mineral Medicine: Pyrolusite-DerivedMnO2 Nanoplatform for Osteo-Angio-Immunomodulatory BoneRepair

Abstract Pyrolusite, a traditional mineral medicine rich in manganese, has long been used to promote fracture healing; however, its complex composition, limited bioavailability, and poorly defined mechanisms have hindered its modernization and clinical translation. Here, we present a nanotechnology-enabled strategy to modernize pyrolusite by constructing a pyrolusite-derived MnO2 nanoplatform for osteo-angio-immunomodulatory bone repair. Pyrolusite nanosuspensions were prepared via a top-down high-energy ball-milling approach and incorporated into an injectable chitosan/β-glycerophosphate thermosensitive hydrogel, thereby enabling precise local delivery and sustained release. By directly comparing natural pyrolusite with its monomeric component MnO2, we elucidated the pharmacological substance basis of pyrolusite-mediated bone repair. Comprehensive in vitro and in vivo studies demonstrated that both materials promote osteogenic differentiation, suppress osteoclastogenesis, enhance angiogenesis, and induce reparative M2 macrophage polarization, thereby reshaping the bone-regeneration microenvironment. Transcriptomic analysis combined with protein–protein interaction mapping and phosphorylation validation identified the PI3K–Akt signaling pathway as a central regulatory hub orchestrating these effects, with MnO2 exhibiting consistently stronger biological activity and pathway activation than natural pyrolusite. In a mouse femoral defect model, MnO2-loaded hydrogels significantly accelerated bone regeneration, improved bone microarchitecture and vascularization, modulated immune responses, and exhibited excellent in vivo biosafety. Collectively, this work establishes a translatable paradigm for upgrading traditional mineral medicine into a mechanism-driven nanotherapeutic platform and highlights the potential of mineral-derived nanomedicine for high-quality bone regeneration.