Herein, an intelligent biodegradable hollow manganese dioxide (H-MnO2) nano-platform is developed for not only tumor microenvironment (TME)-specific imaging and on-demand drug release, but also modulation of hypoxic TME to enhance cancer therapy, resulting in comprehensive effects favoring anti-tumor immune responses. With hollow structures, H-MnO2 nanoshells post modification with polyethylene glycol (PEG) could be co-loaded with a photodynamic agent chlorine e6 (Ce6), and a chemotherapy drug doxorubicin (DOX). The obtained H-MnO2-PEG/C&D would be dissociated under reduced pH within TME to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable in vivo synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Its further combination with checkpoint-blockade therapy would lead to inhibition of tumors at distant sites, promising for tumor metastasis treatment.

Tumor vaccines for cancer prevention and treatment have attracted tremendous interests in the area of cancer immunotherapy in recent years. In this work, we present a strategy to construct cancer vaccines by encapsulating immune-adjuvant nanoparticles with cancer cell membranes modified by mannose. Poly(d,l-lactide- co-glycolide) nanoparticles are first loaded with toll-like receptor 7 agonist, imiquimod (R837). Those adjuvant nanoparticles (NP-R) are then coated with cancer cell membranes (NP-R@M), whose surface proteins could act as tumor-specific antigens. With further modification with mannose moiety (NP-R@M-M), the obtained nanovaccine shows enhanced uptake by antigen presenting cells such as dendritic cells, which would then be stimulated to the maturation status to trigger antitumor immune responses. With great efficacy to delay tumor development as a prevention vaccine, vaccination with such NP-R@M-M in combination with checkpoint-blockade therapy further demonstrates outstanding therapeutic efficacy to treat established tumors. Therefore, our work presents an innovative way to fabricate cancer nanovaccines, which in principle may be applied for a wide range of tumor types.

While immunotherapy has become a highly promising paradigm for cancer treatment in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger antitumor immune responses. However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors. Herein, upconversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist. The obtained multitasking UCNP-Ce6-R837 nanoparticles under near-infrared (NIR) irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses. More significantly, PDT with UCNP-Ce6-R837 in combination with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment. Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell rechallenge. This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence via the immune memory effect.

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H2O2 to generate O2, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation.

Ultrasound (US)-triggered sonodynamic therapy (SDT) that enables noninvasive treatment of large internal tumors has attracted widespread interest. For improvement in the therapeutic responses to SDT, more effective and stable sonosensitizers are still required. Herein, ultrafine titanium monoxide nanorods (TiO1+x NRs) with greatly improved sono-sensitization and Fenton-like catalytic activity were fabricated and used for enhanced SDT. TiO1+x NRs with an ultrafine rodlike structure were successfully prepared and then modified with polyethylene glycol (PEG). Compared to the conventional sonosensitizer, TiO2 nanoparticles, the PEG–TiO1+x NRs resulted in much more efficient US-induced generation of reactive oxygen species (ROS) because of the oxygen-deficient structure of TiO1+x NR, which predominantly serves as the charge trap to limit the recombination of US-triggered electron–hole pairs. Interestingly, PEG–TiO1+x NRs also exhibit horseradish-peroxidase-like nanozyme activity and can produce hydroxyl radicals (•OH) from endogenous H2O2 in the tumor to enable chemodynamic therapy (CDT). Because of their efficient passive retention in tumors post intravenous injection, PEG–TiO1+x NRs can be used as a sonosensitizer and CDT agent for highly effective tumor ablation under US treatment. In addition, no significant long-term toxicity of PEG–TiO1+x NRs was found for the treated mice. This work highlights a new type of titanium-based nanostructure with great performance for tumor SDT.