Puerarin‑Loaded pH‑Responsive ZIF‑90 Nanoparticles Ameliorate Osteoporosis via Enhancing H3K18 Lactylation and Suppressing Aberrant Osteoclast Activation.

Osteoporosis is characterized by dysregulated osteoclast activity, leading to excessive bone resorption and structural damage. In this study, we developed pH-responsive ZIF-90 nanoparticles loaded with puerarin (PU) (ZIF-90@PU) for microenvironment-responsive osteoporosis therapy through epigenetic modulation. Following self-assembly, the nanoparticles underwent dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS); these analyses verified efficient puerarin encapsulation and pH-triggered release. In cell-based experiments, ZIF-90@PU suppressed the differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts while promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Administration of ZIF-90@PU to ovariectomized (OVX) mice produced significant gains in bone mineral density, trabecular architecture, and bone strength without detectable toxicity. Mechanistically, ZIF-90@PU treatment was associated with increased H3K18 lactylation and reduced NFATc1 signaling, accompanied by suppression of osteoclast activation. This study introduces ZIF-90@PU as a novel epigenetic-modulating nanomedicine for osteoporosis treatment.