Oxygen-Evolving Manganese Ferrite Nanovesicles for Hypoxia-Responsive Drug Delivery and Enhanced Cancer Chemoimmunotherapy

Immunological tolerance induced by the hypoxic tumor microenvironment has been a major challenge for current immune checkpoint blockade therapies. Here, a hypoxia-responsive drug delivery nanoplatform is reported to promote chemoimmunotherapy of cancer by overcoming the hypoxia-induced immunological tolerance of tumors. The nanovesicles are assembled from manganese ferrite nanoparticles (MFNs) grafted with hypoxia-responsive amphiphilic polymers as the membrane, with doxorubicin hydrochloride (Dox) loaded in the aqueous cavities. Under hypoxic conditions in tumors, the nanovesicles can rapidly dissociate into individual MFNs to release Dox and induce decomposition of tumor endogenous H₂O₂ for tumor hypoxia relief. As a result, the Dox-loaded nanovesicles display remarkable suppression of primary tumor growth in combination with αPD-L1-mediated checkpoint blockade therapy. Furthermore, the modulation of the hypoxic tumor microenvironment facilitates a long-lasting immunological memory effect to prevent tumor recurrence and metastasis. Therefore, this hypoxia-responsive nanoplatform presents a potential strategy for both local tumor treatment and long-term protection against tumor recurrence.     

Hypoxia-Responsive Photosensitizer Targeting Dual Organelles for Photodynamic Therapy of Tumors

Developing safe and precise image-guided photodynamic therapy is a challenge. In this study, the hypoxic properties of solid tumors are exploited to construct a hypoxia-responsive photosensitizer, TPA-Azo . Introducing the azo group into the photosensitizer TPA-BN with aggregation-induced emission quenches its fluorescence. When the nonfluorescent TPA-Azo enters hypoxic tumors, it is reduced by the overexpressed azoreductase to generate a fluorescent photosensitizer TPA-BN with an amino group that exhibits fluorescence-activatable image-guided photodynamic therapy with dual-organelle (lipid droplets and lysosomes) targeting. This design strategy provides a basis for the development of fluorescence-activatable photosensitizers.     

Hypoxia-Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

The immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia-responsive delivery system is constructed simply by coordinating ferric (Fe³⁺) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia-sensitive dopamine derivative of polyethylene glycol (PEG) using “one-pot” reaction for the “closed-loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia-sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate-cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8⁺ T cells then release interferon γ (IFN-γ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed-loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor-bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.