Nitric Oxide-Based Nanomedicines for Conquering TME Fortress: Say "NO" to Insufficient Tumor Treatment

Almost all cancer treatments are significantly limited by the strong tumor microenvironment (TME) fortress formed by abnormal vasculature, dense extracellular matrix (ECM), multidrug resistance (MDR) system, and immune "cold" environment. In the huge efforts of dismantling the TME fortress, nitric oxide (NO)-based nanomedicines are increasingly occupying a central position and have already been identified as super "strong polygonal warriors" to dismantle TME fortress for efficient cancer treatment, benefiting from NO's unique physicochemical properties and extremely fascinating biological effects. However, there is a paucity of systematic review to elaborate on the progress and fundamental mechanism of NO-based nanomedicines in oncology from this aspect. Herein, the key characteristics of TME fortress and the potential of NO in reprogramming TME are delineated and highlighted. The evolution of NO donors and the advantages of NO-based nanomedicines are discussed subsequently. Moreover, the latest progress of NO-based nanomedicines for solid tumors is comprehensively reviewed, including normalizing tumor vasculature, overcoming ECM barrier, reversing MDR, and reactivating the immunosuppression TME. Lastly, the prospects, limitations, and future directions on NO-based nanomedicines for TME manipulation are discussed to provide new insights into the construction of more applicable anticancer nanomedicines. NO-based nanomedicines for conquering TME fortress: say "NO" to insufficient tumor treatment. NO exerts multiple biological effects through the sGC-cGMP pathway and protein post-translational modification. Importantly, NO released from nanomedicines can cross the barrier through long-distance diffusion, and subsequently dismantle the TME fortress through vascular normalization, ECM demolishment, MDR reversal, and immune activation.image