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.