Comparative study on the redox-responsive properties and antitumor efficacy of polyurethane nanocarriers with mono-, Di-, and trisulfide bonds.

Polyurethane (PU) is considered an ideal nanocarrier for drug delivery due to its excellent biocompatibility and efficient drug-loading capacity. Sulfur bonds (such as monosulfide, disulfide, and trisulfide bonds), have attracted considerable attention in drug delivery systems due to their redox-responsive properties. However, current research primarily focuses on the application of sulfur bonds in prodrug nanoassemblies, where designs rely on specific chemical conjugation groups, limiting their applicability to a narrow range of drug molecules and thus restricting broader utility. Integrating sulfur bonds into polyurethane structures offers a promising approach to enhance carrier biocompatibility while significantly expanding their versatility for delivering various hydrophobic small-molecule drugs. Nevertheless, whether sulfur bonds retain their inherent redox-responsive behavior within a polyurethane requires systematic validation. To address this, we designed and synthesized three amphiphilic polyurethane materials incorporating monosulfide, disulfide, and trisulfide bonds as core components. These polymers self-assembled into nanomicelles, enabling a systematic comparison of their redox-responsive properties. Furthermore, the hydrophobic anticancer drug doxorubicin (DOX) was encapsulated as a model payload to evaluate the in vivo antitumor efficacy of the resulting drug-loaded nanomicelles. Our findings demonstrate that the incorporation of sulfur bonds markedly enhances the redox responsiveness of polyurethane nanocarriers, with the trisulfide bonds exhibiting the most pronounced reduction-sensitive behavior. This study provides deep insights into the influence of sulfur bonds type on the redox-responsive behavior of polyurethane nanomicelles and underscores the exceptional potential of trisulfide bonds in developing redox-responsive polyurethane-based nanocarriers for drug delivery. These results offer critical theoretical and experimental foundations for the design and optimization of smart polyurethane-based drug delivery systems.