Glioma Cell Membrane–Coated CaCO3 Nanoparticles for Localized Postoperative Chemo–Calcium Overload Therapy to Prevent Glioma Recurrence

Background: Postoperative recurrence of glioma remains a major clinical challenge due to the blood-brain barrier and an immunosuppressive tumor microenvironment, necessitating innovative local treatment strategies. Methods: We developed a biomimetic nanoplatform (CaDM) by coating doxorubicin (DOX)-loaded calcium carbonate nanoparticles with a glioma cell membrane. This construct was then integrated with the clinical hemostatic agent Surgiflo to create an in-situ forming depot for localized application into the tumor resection cavity. Results: The CaDM nanoparticles exhibited excellent acid-responsive degradation, enabling simultaneous release of DOX and Ca 2 ⁺ in the tumor microenvironment. This co-delivery initiated a potent synergistic antitumor effect: DOX induced direct cytotoxicity and immunogenic cell death (ICD), while Ca 2 ⁺ influx triggered calcium overload, mitochondrial damage, and tumor vascular thrombosis. Furthermore, CaCO 3 degradation neutralized the acidic microenvironment, downregulating cathepsin B to reverse immunosuppression. In the postoperative glioma model, CaDM@Surgiflo significantly suppressed tumor recurrence and extended the median survival of mice from 14 days to 40 days. Mechanistic studies revealed that this localized therapy amplifies the ICD cascade through the combined action of DOX and Ca 2 ⁺ overload, which in turn robustly activates dendritic cells and augments the infiltration of cytotoxic T lymphocytes. Conclusion: This work presents a readily translatable and multifaceted nanomedicine approach that effectively prevents glioma recurrence through synergistic calcium overload and immunomodulation, offering a promising novel strategy for local tumor treatment. Keywords: Glioma recurrence, CaCO 3 , Surgiflo, Calcium overload, Immunogenic cell death