Manganese oxide nano-platforms in cancer therapy: Recent advances on the development of synergistic strategies targeting the tumor microenvironment

The use of inorganic nanomaterials to tackle and exploit the intrinsic chemical nature of the tumor microenvironment (TME) has emerged as a promising strategy in cancer therapy. Manganese oxide nanoparticles (MnxOy) offer unique advantages in terms of redox properties and specificity towards the TME scenario: low O2 concentrations, mildly acidic pH and high oxidative stress; environmental conditions that often lead to a reduction in the efficacy of cancer treatments. MnxOy-based nanoplatforms have recently demonstrated exciting properties as inorganic nanocatalysts to operate under TME constraints. Alternatively, Mn-nanocatalysts have also displayed synergistic anticancer response in combination with other active co-adjuvant elements (drugs, enzymes or nanomaterials). The aim of this review is to provide new insights on the main functionalities of Mn-based nanomaterials applied to cancer therapy. We analyze its capacity as oxygen supplier in hypoxic scenarios, its role to induce the selective depletion of glutathione (GSH) to maximize cell stress or its capacity to promote starvation therapy via glucose oxidation. We aim at providing an insightful view of the operating mechanisms behind each of these critical processes and highlight the versatility and catalytic richness of Mn-based nanoparticles in this developing field. We also provide a general and comprehensive analysis of the Mn fate when trafficking through the intracellular levels.