Dual-locked SO2/nanozyme delivery nanoplatform for programmed synergistic gas/chemodynamic anticancer therapy

Abstract

SO₂ gas-therapy provides sustained assistance for augmenting the efficacy of ROS-based modalities due to its powerful tumor microenvironment-reversing capabilities. However, the inefficient delivery and insufficient generation of SO₂ have greatly limited the efficacy of SO₂ therapy. Herein, we designed a programmed-responsive SO₂/nanozyme synergistic therapeutic nanomedicine based on the polypeptide-type copolymer of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL). By taking advantage of the abundant amine groups on the PLL blocks, a dual-locked SO₂ releasing system was fabricated by grafting SO₂ prodrug onto the PLL blocks through GSH-responsive covalent bonds and crosslinking the remaining amine groups with disulfide-connectors to form an outer stimulation-responsive shell. Such a dual encapsulation effectively prevented the premature release of SO₂ in normal cells and guaranteed its timely and sustained release, making the SO₂ therapeutic processes finely coordinate with the catalytic processes of nanozymes loaded in the micellar core. The well-matching of SO₂ and nanozyme resulted in the efficaciously remodeling of the tumor redox microenvironment, thus significantly enhancing the overall efficacy of chemodynamic therapy (CDT). This optimized multimodal cooperation strategy provides delicate control for improving the synergistic therapeutic efficiencies, which is anticipated to advance the ROS-based cancer treatments.