Zwitterionic Polymer Coating of Sulfur Dioxide‐Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy

Abstract Multiple drug resistance (MDR) exhibited by cancer cells and low intratumor accumulation of chemotherapeutics are the main obstacles in cancer chemotherapy. Herein, the preparation of a redox‐responsive sulfur dioxide (SO₂)‐releasing nanosystem, with high SO₂‐loading capacity, aimed at improving the treatment efficacy of cancers exhibiting MDR is described. The multifunctional nanomedicine (MON‐DN@PCBMA‐DOX) is designed and constructed by coating mesoporous organosilica nanoparticles with a zwitterionic polymer, poly(carboxybetaine methacrylate) (PCBMA), which can concurrently load SO₂ prodrug molecules (DN, 2,4‐dinitrobenzenesulfonylchloride) and chemotherapeutics (DOX, doxorubicin). The generated SO₂ molecules can sensitize cells to chemotherapy and overcome the MDR by downregulating the expression of P‐glycoprotein. Furthermore, the PCBMA coating prolongs the blood circulation time of the inner core, leading to an increased intratumor accumulation of the nanomedicine. Owing to the prolonged blood circulation, enhanced tumor accumulation, and SO₂ sensitization of cells to chemotherapy, the nanomedicine exhibits excellent tumor suppression with a tumor inhibition rate of 94.8%, and might provide a new platform for cancer therapy.