Environmentally Self-Adaptative Nanocarriers Suppress Glioma Proliferation and Stemness via Codelivery of shCD163 and Doxorubicin

Gliomasdevastating intracranial tumors with a dismal outcomeare in dire need of innovative treatment. Although nanodrugs have been utilized as a target therapy for certain types of solid tumors, their therapeutic effects in gliomas are limited due to the complications of the systemic circulation, blood–brain barrier (BBB), and specific glioma environment. Thus, we aimed to establish a nanoliposome adaptable to different environments by codelivery of shCD163 and doxorubicin (DOX) to treat gliomas. In this study, we first synthesized pH-sensitive DSPE-cRGD-Hz-PEG₂₀₀₀ to form an environmentally self-adaptative nanoliposome (cRGD-DDD Lip) via a thin film method. We used in vitro BBB models, in vitro cell uptake experiments, and in vivo biodistribution assays to confirm the long circulation time and low cell uptake of the cRGD-DDD Lip as a result of the poly­(ethylene glycol) (PEG) shell of cRGD-DDD Lip in the neutral pH systemic circulation. Moreover, the cRGD-DDD Lip bypassed the BBB and attached to the intracranial glioma following the removal of the PEG shell and the exposure of cRGD to the weakly acidic tumor microenvironment. We further assembled the shCD163/DOX@cRGD-DDD Lip through cRGD-DDD Lip loading of shCD163 and DOX. In vitro, cell proliferation and self-renewal of glioma cells were inhibited by the shCD163/DOX@cRGD-DDD Lip due to the toxicity of DOX and the suppression of shCD163 via the CD163 pathway. In vivo, the shCD163/DOX@cRGD-DDD Lip disturbed the progression of in situ gliomas by inhibiting the growth and stemness of glioma cells and prevented the recurrence of gliomas after resection. In conclusion, the cRGD-DDD Lip may be a promising nanodrug-loading platform to cope with different environments and the shCD163/DOX@cRGD-DDD Lip may potentially be a novel nanodrug for glioma therapy.