Tumor microenvironment-responsive manganese-based nanomaterials for cancer treatment

Tumor microenvironment (TME), which characteristically displays hypoxia, immunosuppression, reprogramming metabolism and mild acidity, has been considered as an ideal target for cancer treatment. In the past few decades, an increasing number of TME-responsive nanomaterials have been developed. Among them, manganese-based nanomaterials (Mn-based NMs) have stimulated growing attentions owing to their unique characteristics such as tunable structures/morphologies, novel magnetic/optical properties, strong catalytic activities and good biodegradability. More importantly, they have excellent TME targetability and significant potential to modulate TME. In this review, we introduce different types of Mn-based NMs and discuss their strategies to modulate the TME, such as oxygen generation, pH value increase, reactive oxygen species production, glutathione/hydrogen peroxide depletion, glucose exhaustion, and innate or adaptive immunity activation, which are always accompanied by increased imaging signals for response monitoring. Such great advantages endow Mn-based NMs a broad range of applications in TME-responsive cancer therapies, including photodynamic therapy (PDT), sonodynamic therapy (SDT), radiotherapy, starvation therapy, chemodynamic therapy (CDT), ferroptosis-mediated therapy, chemotherapy, gene therapy, gas therapy and immunotherapy. Besides, cancer therapies through generating heat in TME are also outlined, including magnetic hyperthermia, microwave thermal therapy (MTT), microwave dynamic therapy (MDT) and photothermal therapy (PTT). Representative examples of each treatment modality and combination therapy are presented. Finally, future opportunities and challenges of TME-responsive Mn-based NMs for cancer treatment are tentatively proposed.