Dual-Responsive Bionic Transformable Silica-Based Nanoparticles Promoting Macrophage M1 Polarization for Ameliorating Glioblastoma Immunosuppressive Microenvironment

Immunotherapy for glioblastoma (GBM) remains a major challenge due to the immunosuppressive tumor microenvironment, in which tumor-associated macrophages (TAMs) are a key contributor. Repolarizing TAMs from the pro-tumor M2 phenotype to the antitumor M1 phenotype offers a promising therapeutic strategy. To promote M1 polarization of TAMs and achieve stimuli-responsive controlled drug release for GBM treatment, we developed a glutathione (GSH)/pH dual-responsive bionic transformable silica-based nanoparticle vSiO 2 @JS-K/TDTCD-TA-Fe 3+ @Ang-2 which named as VTKFA. Within this nanoparticle, the nitric oxide (NO) prodrug JS-K serves as the pharmacological agent to induce TAMs repolarization. For real-time monitoring of JS-K release, we designed a NO-activated probe, TDTCD. Virus-like silica nanoparticles (vSiO 2 ) were then engineered to coload JS-K and TDTCD. A ferric–tannic network (TA–Fe 3+ ) complexed with Angiopep-2 (Ang-2) was coated onto the vSiO 2 surface, masking its original morphology. This coating disassembles under the acidic tumor microenvironment, re-exposing the bionic virus-like structure to promote rapid cellular uptake and enhanced tumor penetration. Subsequently, intracellular GSH triggers vSiO 2 degradation and JS-K release, generating NO and simultaneously activating TDTCD fluorescence. The released NO acts synergistically with hydroxyl radicals (•OH) produced via the Fenton reaction during the reduction of Fe 3+ to Fe 2+ to drive TAMs reprogramming to the M1 phenotype. This multifunctional nanoparticle, enabling both stimuli-responsive drug release and effective TAMs repolarization, is expected to alleviate the immunosuppressive microenvironment and suppress GBM progression.