Surgical resection and postoperative radiotherapy remained the most common therapeutic modalities for malignant tumors. However, tumor recurrence after receiving such combination is difficult to be avoided because of high invasiveness and radiation resistance of cancer cells during long-term therapy. Hydrogels, as novel local drug delivery systems, presented excellent biocompatibility, high drug loading capacity and sustained drug release property. Compared with conventional drug formulations, hydrogels are able to be administered intraoperatively and directly release the entrapped therapeutic agents to the unresectable tumor sites. Therefore, hydrogel-based local drug delivery systems have their unique advantages especially in sensitizing postoperative radiotherapy. In this context, classification and biological properties of hydrogels were firstly introduced. Then, recent progress and application of hydrogels for postoperative radiotherapy were summarized. Finally, the prospects and challenges of hydrogels in postoperative radiotherapy were discussed.

Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II–mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment. Graphical Abstract

Stable long-wavelength emission carbon dots (R-CDs) have been synthesized to enable effectively visualize deep brain glioblastoma (GBM) by a liposome-formulated delivery system.

Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood–brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.