MRgFUS-enabled nanogel platform for synergstic chemo-immunotherapy in glioblastoma

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis and limited responsiveness to temozolomide (TMZ)-based chemoradiotherapy. Treatment remains hindered by the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), acquired TMZ resistance, and an immunosuppressive tumor microenvironment. To overcome these challenges, we developed a multifunctional nanogel platform for co-delivering TMZ and PD-L1-targeting siRNA. TMZ not only exerts direct cytotoxicity against GBM cells but also induces immunogenic cell death (ICD), promoting the release of damage-associated molecular patterns and tumor-associated antigens for antitumor immune activation. Meanwhile, siRNA-mediated PD-L1 silencing alleviates immune evasion and potentiates T-cell-mediated antitumor responses. Magnetic resonance-guided focused ultrasound (MRgFUS) was employed to locally disrupt the BBB/BBTB and enhance nanogel penetration. Ultrasmall iron oxide nanoparticles (USIO) provided T₁-weighted MRI contrast for real-time monitoring of nanogel distribution and tumor targeting. Distinct from conventional FUS-nanoparticle platforms, this MRgFUS-guided theranostic nanogel integrates TMZ-based chemotherapy, TMZ-induced ICD, siRNA-mediated PD-L1 silencing, and MRI-traceable delivery into a single platform, enabling image-guided, spatiotemporally precise chemo-immunotherapy for glioblastoma.