Peptide‐Modified Fluorinated Polymeric Carriers for Targeted Delivery of β‐GP to Enhance Bone Regeneration

ABSTRACT Current treatments for osteoporosis and osteoporotic fractures, such as bisphosphonates and teriparatide, are limited by poor bone‐targeting and systemic toxicity. To address these issues, we developed a bone‐targeted nanodelivery platform (FPBE) by encapsulating β‐glycerophosphate (β‐GP) in a fluorinated polyethylenimine carrier. The platform was further functionalized with the E7 peptides to enhance the affinity for mesenchymal stem cells (MSCs) and improve bone marrow targeting. Biocompatibility and delivery efficiency were optimized by the degree of screening fluorination. Single‐cell RNA sequencing revealed that FPBE upregulates Wnt/β‐catenin, driving MSC osteogenic and chondrogenic differentiation to support regenerative processes. In postmenopausal mice, systemic FPBE increased bone mineral density (BMD), matching zoledronic acid levels with fewer side effects. In non‐human primates, FPBE increased BMD by 83.07% (males) and 55.92% (females), with serum analyses confirming its efficacy and safety. This nanoplatform—which delivers β‐GP to restore phosphate balance—provides a cost‐effective therapy for osteoporosis and osteoporotic fracture repair, with strong potential for clinical application.