Bone metabolism is a dynamic process regulated by the interplay between osteoblasts and osteoclasts (OCs), which is essential for maintaining bone homeostasis, and ensuring skeletal integrity and normal function. However, factors such as inflammation, oxidative stress, and hormonal imbalances often lead to excessive OC formation, resulting in osteolytic diseases that severely impact patients' physical and mental health. Current therapeutic options, including non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates, are limited by side effects and high costs. In recent years, increasing attention has been directed toward developing novel drugs and materials aimed at inhibiting OC activity and associated inflammatory responses. This study focuses on Prussian Blue nanoparticles (PBNPs), a novel class of nanozymes with promising antioxidant and anti-inflammatory properties. In vitro experiments demonstrate that PBNPs significantly suppressed LPS-induced oxidative stress and inflammatory cytokine release in macrophages, downregulate the expression of OC-related genes, and effectively inhibit the receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMMs) into OCs. Mechanistically, PBNPs activated nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-oxidative product expression. In vivo studies further reveal that PBNPs alleviated LPS-induced cranial bone resorption in mice, reduced local inflammatory responses in the calvaria, and upregulated the expression of the endogenous antioxidant protein Nrf2. Collectively, these findings highlight the potential of PBNPs as a novel therapeutic strategy for inflammatory osteolytic diseases by modulating oxidative stress and inflammatory responses in macrophages and OCs, offering new insights for clinical applications.Copyright © 2025 Elsevier B.V. All rights reserved.