Small molecules for great solutions: Can nitric oxide-releasing nanomaterials overcome drug resistance in chemotherapy?

Nitric oxide (NO) is an endogenous free radical that controls important physiological and pathophysiological processes, including a role in cancer biology. NO can have a direct toxic effect on tumors, or it can sensitize cancer cells and contribute to the reversal of multidrug resistance (MDR). As NO is a gas and free radical, NO donors have been investigated for their anticancer effects. In recent years, the combination of NO donors with nanomaterials has been emerging as a promising strategy to promote spatial-temporal NO release/generation directly at the target site of application (tumor tissue). Smart nanocarriers that are able to release NO under controlled stimuli have been extensively developed. Moreover, important publications have demonstrated the promising applications of NO-releasing nanomaterials in combination with traditional chemotherapies in which NO can sensitize cancer cells. In this direction, this review presents and discusses the recent progress in the design of versatile nanocarriers that are able to release/generate therapeutic amounts of NO and which can be combined with conventional anticancer therapies. These nanocarriers have the ability to release NO on-demand by external stimuli such as pH, wave, or light exposure. In addition, the possible mechanisms of NO in sensitizing tumor tissue and the impact and challenges of nanomaterials in cancer treatment are also presented and discussed. The biological and pharmacological aspects of NO donors in cancer are discussed. Finally, challenges and perspectives in the development of versatile nanoplatforms to efficiently deliver NO in clinical cancer treatment are highlighted.