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Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.

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Although nanomedicines can passively target tumor through the enhanced permeability and retention (EPR) effect, their distribution and retention are limited by complex tumor microenvironment. Herein, a self-delivery supramolecular nanoplatform with shape-transforming capacity (Ce6-CD/ Fc-pep-PEG) is constructed by the host-guest interaction between chlorin e6-conjugated β-cyclodextrin (Ce6-CD) and ferrocene-modified FFVLG 3 C-PEG conjugates (Fc-pep-PEG). Following passive accumulation mediated by the EPR effect, hydrophobic Fc is oxidized to water-soluble Fc + by endogenous ROS in tumor sites. The resulting Fc + -pep-PEG fragment dissociated from Ce6-CD and recombined to nanofibers through the intermolecular hydrogen bonds among FFVLG 3 C peptide chains, thus enhancing the retention. Meanwhile, the Ce6-CD fragment still maintained the form of spherical micelles with a relatively smaller size to penetrate into the deep tumor regions. Moreover, the cascade Fenton reaction catalyzed by Fc generated •OH and O 2 to relieve hypoxia and amplify PDT efficiency. In turn, ROS generated by PDT promoted shape-transformation and continuous occurrence of Fenton reaction. In vitro and in vivo evaluations verify that through the positive feedback loop, Ce6-CD/ Fc-pep-PEG can induce a potent antitumor immune response and achieve ROS-potentiated elimination of primary tumor and bone metastasis.