Recent advances in sulfur dioxide releasing nanoplatforms for cancer therapy

Sulfur dioxide (SO2), long considered to be a harmful atmospheric pollutant, has recently been posited as the fourth gasotransmitter, as it is produced endogenously in mammals and has important pathophysiological effects. The field of tumor therapy has witnessed a paradigm shift with the emergence of SO2-based gas therapy. This has been possible because SO2 is a potent glutathione consumer that can promote the production of reactive oxygen species, eventually leading to oxidative-stress-induced cancer cell death. Nevertheless, this therapeutic gas cannot be directly administrated in gaseous form. Thus, various nano formulations incorporating SO2 donors or prodrugs capable of storing and releasing SO2 have been developed in an attempt to achieve active/passive intratumoral accumulation and SO2 release in the tumor microenvironment. In this review article, the advances over the past decade in nanoplatforms incorporating sulfur SO2 prodrugs to provide controlled release of SO2 for cancer therapy are summarized. We first describe the synthesis of polypeptide SO2 prodrugs to overcome multiple drug resistance that was pioneered by our group, followed by other macromolecular SO2 prodrug structures that self-assemble into nanoparticles for tumor therapy. Second, we describe nanoplatforms composed of various small-molecule SO2 donors with endogenous or exogenous stimuli responsiveness, including thiol activated, acid-sensitive, and ultraviolet or near-infrared light-responsive SO2 donors, which have been used for tumor inhibition. Combinations of SO2 gas therapy with photodynamic therapy, chemotherapy, photothermal therapy, sonodynamic therapy, and nanocatalytic tumor therapy are also presented. Finally, we discuss the current limitations and challenges and the future outlook for SO2-based gas therapy. STATEMENT OF SIGNIFICANCE: Gas therapy is attracting increasing attention in the scientific community because it is a highly promising strategy against cancer owing to its inherent biosafety and avoidance of drug resistance. Sulfur dioxide (SO2) is recently found to be produced endogenously in mammals with important pathophysiological effects. This review summarizes recent advances in SO2 releasing nanosystems for cancer therapy, including polymeric prodrugs, endogenous or exogenous stimulus-activated SO2 donors delivered by nanoplatform and combination therapy strategies.