Macrophage Membrane-Camouflaged Nanoparticles for Synergistic Gene-Phototherapy in Glioblastoma

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. Its treatment efficacy is largely limited by the blood–brain barrier (BBB). Given their excellent capacity to penetrate the BBB, macrophage membrane (MM)-modified nanomedicine systems represent a promising strategy to overcome this obstacle. MM-camouflaged nanoparticles (NPs) (siSTAT3–IR780@M) were prepared by co-loading the photosensitizer IR780 with siSTAT3 via electrostatic adsorption, followed by camouflage with an MM. Their physical characteristics were characterized by transmission electron microscopy, dynamic light scattering, and ultraviolet-visible (UV-Vis) spectroscopy. Biosafety and BBB penetration were evaluated through hemolysis, CCK-8, cellular uptake assays, and an in vitro BBB model. In vitro antitumor effects were assessed via DCFH-DA probe, western blot, and Annexin V/PI staining. In vivo biodistribution, antitumor efficacy, and biosafety were investigated using a xenograft GBM nude mouse model and IVIS imaging. The fabricated siSTAT3–IR780@M NPs exhibited a spherical morphology, favorable photodynamic properties, and a uniform size distribution. In vitro, these NPs efficiently enhanced uptake by U87 MG cells, effectively traversed the BBB model, significantly elevated intracellular reactive oxygen species levels, suppressed STAT3 protein expression, and induced apoptosis. In vivo, the NPs showed significant accumulation in brain tumor tissues. Upon near-infrared irradiation, tumor growth was substantially inhibited without inducing obvious adverse effects. siSTAT3–IR780@M NPs demonstrate excellent BBB penetration and tumor-targeting ability. They synergistically enhance GBM treatment through combining gene silencing and photodynamic therapy. This study highlights the strong potential of siSTAT3–IR780@M for clinical translation. • Macrophage membrane camouflage enhances blood–brain barrier (BBB) penetration and tumor targeting of nanodrugs, significantly overcoming a key bottleneck in glioblastoma (GBM) treatment. • Combined gene silencing (siSTAT3) and photodynamic therapy (PDT) markedly enhances tumor suppression. • In vitro and in vivo experiments demonstrate low toxicity and high antitumor efficacy of the nanodrugs, indicating good biosafety and clinical translation potential.