Multifunctional PVCL nanogels enable magnetic resonance imaging and immunostimulated radiotherapy of orthotopic glioblastoma

Despite radiotherapy (RT) is considered as an indispensable treatment that improves clinical symptoms and survival rates of glioblastoma multiforme (GBM), the overall survival time of GBM based on multimodal treatment synergic with RT is still unsatisfying. Herein, we designed an immunostimulated nanoplatform consisting of MnO₂ and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) within the poly(N-vinylcaprolactam) nanogels (PVCL-MnO₂-CpG NGs) for magnetic resonance imaging (MRI)-guided immuno-activated RT against GBM. In this system, I) CpG ODNs can be protected by PVCL NGs from degradation, which can increase the cellular uptake by immune cells and promote the activation of Toll-like receptor 9 (TLR9) pathway, thus enhance the immune responses to assist the therapeutic efficacy of tumour RT. II) PVCL-MnO₂-CpG NGs are able to be dissociated to release Mn²⁺ in the tumour microenvironment, resulting in excellent T₁-weighted tumour MRI along with the activation of cyclic GMP–AMP synthase/stimulator of interferon genes (cGAS/STING) pathway and elevated secretion of type-I interferons (IFN-I) in the downstream. III) MnO₂ can also act as nanoenzyme to relieve tumour radioresistance through increasing the reactive oxygen species (ROS) level. Compared with RT alone, combinational immunoradiotherapy remarkably promotes the proportion of cytotoxic T cells (CD3⁺CD8⁺) and exhibits systemic therapeutic efficacy. Thus, MnO₂ and CpG ODNs-loaded PVCL NGs may serve as a potential theranostic platform for MRI-guided immunostimulated RT of GBM.