A Biomimetic Multimodal Nanoplatform Combining Neutrophil-Coated Two-Dimensional Metalloporphyrinic Framework Nanosheet and Exendin-4 to Treat Obesity-Related Osteoporosis

Background Obesity-induced osteoporosis is a prevalent complication among obese individuals. Conventional anti-osteoporosis medications often lack therapeutic specificity and may exacerbate lipid metabolism disorders. Consequently, identifying suitable pharmacological interventions for obesity-induced osteoporosis, elucidating its underlying biological mechanisms, and developing nanodrug delivery systems with enhanced biocompatibility and targeted delivery remain significant challenges. Methods This study reveals that the pathogenesis of obesity-induced osteoporosis is primarily driven by excessive mitophagy. Notably, Exendin-4 (Ex-4) has been shown to ameliorate mitophagy and mitigate obesity-induced osteoporosis. The nanocomposite DSPE-PEG-ALN (DPA)@Neutrophil membrane (NM)@Cu-TCPP(Zn)/Ex-4 (CTZE), characterized by high biocompatibility and reactive oxygen species (ROS) responsiveness, effectively targets bone tissue, reduces ROS levels, and regulates the release of Cu 2+ , Zn 2+ , Ex-4, and Alendronate (ALN). This composite interferes with B-cell lymphoma-2 (BCL2)- Beclin-1 (BECN1) binding via the tet methylcytosine dioxygenase 2 (TET2)/ PTEN-induced putative kinase protein 1 (PINK1)/Parkin (E3 ubiquitin-protein ligase parkin) pathway, thereby promoting osteoblast differentiation and mineralization. The safety and efficacy of this nano-delivery platform were validated in a mouse model of obesity-induced osteoporosis. Conclusions In summary, our study illustrates that excessive mitophagy plays a crucial role in obesity-induced osteoporosis. Furthermore, DPA@NM@CTZE exhibits significant potential for the precise treatment of obesity-induced osteoporosis, mitigating the side effects of Ex-4, and enhancing the bone microenvironment.