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.

Radiation therapy (RT) including external beam radiotherapy (EBRT) and internal radioisotope therapy (RIT) has been widely used for clinical cancer treatment. However, owing to the low radiation absorption of tumors, high doses of ionizing radiations are often needed during RT, leading to severe damages to normal tissues adjacent to tumors. Meanwhile, the RT efficacies are limited by different mechanisms, among which the tumor hypoxia-associated radiation resistance is a well-known one, as there exists hypoxia inside most solid tumors while oxygen is essential to enhance radiation-induced DNA damages. With the development in nanotechnology, there have been great interests in using nanomedicine strategies to enhance radiation responses of tumors. Nanomaterials containing high-Z elements to absorb radiation rays (e.g. X-ray) can act as radio-sensitizers to deposit radiation energy within tumors and promote treatment efficacy. Nanoscale carriers are able to deliver therapeutic radioisotopes into tumors for internal RIT, or chemotherapeutic drugs for synergistically combined chemo-radiotherapy. As uncovered in recent studies, the tumor microenvironment could be modulated by various nanomedicine approaches to overcome hypoxia-associated radiation resistance. Herein, the authors will summarize the applications of nanomedicine for RT cancer treatment, and pay particular attention to the latest development of 'advanced materials' for enhanced cancer RT.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) usually requires hyperthermia to >50 °C for effective tumor ablation, which can potentially induce inflammatory disease and heating damage of normal organs nearby, while tumor lesions without sufficient heating (e.g., the internal part) may survive after treatment. Achieving effective tumor killing under relatively low temperatures is thus critical toward successful clinical use of PTT. Herein, we design a simple strategy to fabricate poly(ethylene glycol) (PEG)-modified one-dimensional nanoscale coordination polymers (1D-NCPs) with intrinsic biodegradability, large surface area, pH-responsive behaviors, and versatile theranostic functions. With NCPs consisting of Mn2+/indocyanine green (ICG) as the example, Mn-ICG@pHis-PEG display efficient pH-responsive tumor retention after systemic administration and then load Gambogic acid (GA), a natural inhibitor of heat-shock protein 90 (Hsp90) that plays an essential role for cells to resist heating-induced damage. Such Mn-ICG@pHis-PEG/GA under a mild NIR-triggered heating is able to induce effective apoptosis of tumor cells, realizing low-temperature PTT (~43 °C) with excellent tumor destruction efficacy. This work not only develops a facile approach to fabricate PEGylated 1D-NCPs with tumor-specific pH responsiveness and theranostic functionalities, but also presents a unique low-temperature PTT strategy to kill cancer in a highly effective and minimally invasive manner.

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