一种导航纳米平台能够实现精确的siRNA递送，为强效治疗胶质母细胞瘤提供新方案。

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor. Tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and inefficient drug delivery into tumor cells lead to limited therapeutic efficacy against GBM. In this work, an siRNA targeting chitinase 3-like protein 1 (CHI3L1), a key regulator of GBM progression and a promising therapeutic target, was synthesized, and a siCHI3L1-loaded navigated nanoplatform, termed sDT-LNP, for GBM dual-targeting delivery was constructed. Among the components of sDT-LNP, Aβ 25–35 can bind to the receptor for advanced glycation end-products (RAGEs) on the blood–brain barrier (BBB) and mediate sDT-LNP to cross BBB via receptor-mediated transcytosis and accumulate in the brain. Aβ 25–35 was detached in endosomes and the tumor-penetrating peptide CGKRK on sDT-LNP was exposed, enabling deep penetration in tumors and selective internalization by tumor cells. In an orthotopic GBM mouse model, profiting from the tissue-to-cell cascade targeting ability, sDT-LNP downregulated about 76.0% of CHI3L1 expression in tumor cells, inducing tumor cell apoptosis and sensitizing them to temozolomide (TMZ), and participated in the reprogramming of TME. The combination of sDT-LNP and TMZ achieved significant tumor inhibition and prolonged survival of tumor-bearing mice. This study designed a precise GBM-targeting siRNA delivery system and provided an effective strategy for GBM therapy.