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

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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 in vitro BBB model and glioma cell models were employed to evaluate BBB permeability, cellular uptake, cytotoxicity, cell cycle arrest, apoptosis, and inflammatory cytokine secretion. Subcutaneous and orthotopic glioma mouse models were created to investigate in vivo tumor targeting, antitumor activity, survival benefit, and systemic biosafety. Flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and histopathological staining were employed to examine the regulatory impact of the nanosystem on the tumor immune microenvironment. 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). In vitro studies revealed that the formulation significantly inhibited glioma cell proliferation and migration, induced cell apoptosis, and rejuvenated T cell exhaustion. In vivo findings revealed that PD-1-MSCs-ELE/CTX@BLIP exhibited significant accumulation in tumor tissues, remarkably suppressed tumor proliferation, and markedly prolonged the survival duration (57.52%) of orthotopic glioma-bearing mice. Mechanistically, it blocked the PD-1/PD-L1 immune checkpoint pathway, increased intratumoral CD8+ T cell infiltration, upregulated pro-inflammatory cytokine IFN-γ, and downregulated immunosuppressive factors IL-1β, thereby remodeling the immunosuppressive TME. Furthermore, major organs, blood, and liver/kidney function tests revealed no systemic toxicity. 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.

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