Hyaluronic acid-based biomaterials for the treatment of osteosarcoma and postoperative bone repair

Osteosarcoma is a common malignant bone tumor in adolescents. Clinical treatments face major challenges, including postoperative recurrence, refractory bone defects, and inadequate targeting of chemotherapeutic drugs. Hyaluronic acid (HA), a natural component of the human extracellular matrix, serves as an ideal material for integrating osteosarcoma therapy and postoperative bone regeneration, attributed to its unique properties including CD44-mediated tumor targeting, tumor microenvironment (TME)-responsive degradation, excellent biocompatibility, and functional tunability. This review summarizes recent advances in HA-based materials for osteosarcoma therapy. HA acts as a versatile carrier for chemotherapeutic drugs (e.g., doxorubicin (DOX), cisplatin (CDDP)) and therapeutic nucleic acids, via nanoparticles, liposomes, or hydrogels. These carriers enhance intratumoral drug accumulation, reduce systemic toxicity, evade immune recognition, and facilitate intracellular drug delivery. Incorporating bioactive glass or magnesium-based nanomaterials into HA constructs a multifunctional therapy-regeneration system, which simultaneously inhibits tumor growth and promotes bone regeneration, addressing postoperative bone defects. Furthermore, we analyze key obstacles to clinical translation, such as rapid degradation, insufficient hydrogel mechanical strength, and poor sterilization compatibility, and propose solutions including chemical cross-linking and composite modification. These insights provide valuable guidance for the precise design of HA-based biomaterials and their clinical translation, aligning with the demand for therapy-repair integration in regenerative medicine.