Biomimetic PD-1-MSCs membrane-engineered nanoparticles for enhanced blood-brain barrier penetration and anti- glioma therapy.

Objective: Glioma is the most common and aggressive primary intracranial tumor. Its clinical management is substantially hindered by the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (TME). This study aimed to construct PD-1-functionalized mesenchymal stem cell (MSC) membrane biomimetic nanoparticles co-loaded with elemene and cabazitaxel (PD-1-MSCs-ELE/CTX@BLIP) and investigate their capacity to penetrate the BBB, target gliomas, and their combined chemoimmunotherapeutic efficacy and related mechanisms. Methods: Genetic engineering was utilized to create PD-1-overexpressing MSCs, and the derived cell membranes were extracted to fabricate biomimetic nanoparticles. A series of characterizations was performed to ascertain the particle size, zeta potential, encapsulation efficiency, stability, and biosafety of the nanoparticles. An Results: The synthesized PD-1-MSCs-ELE/CTX@BLIP exhibited uniform particle size, high drug encapsulation efficacy, and excellent storage stability and biocompatibility. Leveraging MSC biomimetic modification and the PD-1/PD-L1 axis, the nanoparticles exhibited significant BBB penetration ability and active targeting capability toward glioma cells (8.57-fold). Conclusion: The PD-1-modified MSC membrane biomimetic nanoplatform integrates targeted chemotherapy and immune checkpoint inhibition. It efficiently crosses the BBB, specifically accumulates in glioma tissues, exerts potent antitumor effects, and improves the tumor immune microenvironment with favorable biosafety. This study provides a novel, promising biomimetic chemoimmunotherapeutic approach for precise glioma treatment.