Hierarchically Structured Hydroxyapatite Particles Facilitate the Enhanced Integration and Selective Anti‐Tumor Effects of Amphiphilic Prodrug for Osteosarcoma Therapy

Abstract Efficient delivery of cargo into target cells is a formidable challenge in modern medicine. Despite the great promise of biomimetic hydroxyapatite (HA) particles in tissue engineering, their potential applications in bone tumor therapy, particularly their structure–function relationships in cargo delivery to target cells, have not yet been well explored. In this study, biomimetic multifunctional composite microparticles (Bm‐cMPs) are developed by integrating an amphiphilic prodrug of curcumin with hierarchically structured HA microspheres (Hs‐hMPs). Then, the effects of the hierarchical structure of vehicles on the integration and delivery of cargo as well as the anti‐osteosarcoma (OS) effect of the composite are determined. Different hierarchical structures of the vehicles strongly influence the self‐assembly behavior of the prodrug. The flake‐like crystals of Hs‐hMPs enable the highest loading capacity and enhance the stability of the cargo. Compared to the normal cells, OS cells exhibit 3.56‐times better uptake of flake‐like Hs‐hMPs, facilitating the selective anti‐tumor effect of the prodrug. Moreover, Bm‐cMPs suppress tumor growth and metastasis by promoting apoptosis and inhibiting cell proliferation and tumor vascularization. The findings shed light on the potential application of Bm‐cMPs and suggest a feasible strategy for developing an effective targeted therapy platform using hierarchically structured minerals for OS treatment.