Bionanoparticles with In Situ Nitric Oxide Release for Precise Modulation of ER‐TRPV1 Ion Channels in Multimodal Killing of Glioblastoma

Abstract Glioblastoma (GBM) with highly immunosuppressive tumor microenvironment is a significant factor contributing to its treatment resistance and low survival rate. The activation of the transient receptor potential vanilloid 1 (TRPV1) ion channel, which is overexpressed on the endoplasmic reticulum (ER) of GBM cells, governs the control of multi‐organelle stress pathway branches to inhibit GBM expansion. Precise modulation of ER‐TRPV1 is considered an effective strategy for inhibition of GBM. As an effective intracellular and extracellular second messenger, nitric oxide (•NO) activates the TRPV1 ion channel through nitrosylation of cysteine residues. However, the short lifespan and limited effective range of •NO makes it challenging to achieve precise regulation of ER‐TRPV1. Herein, a biomimetic upconversion nanoassembly (M‐UCN‐T) is constructed, which encapsulates an organic •NO donor and is coated with homologous tumor‐targeting cell membrane and ER‐targeting peptide. In response to near‐infrared light and glutathione, M‐UCN‐T releases •NO in situ to activate the ER‐TRPV1 ion channels. This study developed a •NO‐targeted release nanoplatform with stepwise targeting functions, which allow for the precise modulation of ER‐TPRV1 in GBM through in situ release of •NO. This approach induces multi‐organelle stress signaling pathways, ultimately resulting in multi‐modal killing of tumor cells.