A Polymeric Vesicle System for Combined Lung Cancer Therapy through Chemotherapy and Vasculature Normalization

Lung cancer remains a great threat to human health despite the rapid development of various therapeutic methods. Chemotherapy continues to be the most commonly employed treatment for lung cancer; however, it often suffers from low drug delivery efficiency and severe side effects. To enhance the therapeutic efficacy of chemotherapy, we developed a novel strategy that integrates tumor vasculature normalization with the co-delivery of therapeutic agents. This strategy employs a diblock polymeric vesicle with a reduction-sensitive linkage. Paclitaxel (PTX) is encapsulated in the bilayer, while an acid-sensitive nitric oxide (NO) precursor, DETA NONOate, and zinc oxide nanoparticles (ZnO NPs) are loaded into the central cavity. The resulting nanosystem, (ZnO,NONO)@Ves-PTX, is designed to release NO under the acidic conditions typical of the tumor microenvironment (TME) and intracellular environment. The released NO in the TME inhibits angiogenesis, thereby facilitating the delivery and distribution of therapeutic agents. Upon internalization by tumor cells, (ZnO,NONO)@Ves-PTX decomposes in response to intracellular glutathione (GSH), releasing the loaded agents. DETA NONOate and ZnO NPs generate NO and Zn²⁺ ions, respectively, at the intracellular pH, which synergistically inhibit tumor growth alongside PTX. This combined therapeutic approach demonstrated remarkable potential in improving the chemotherapeutic efficacy for lung cancer, offering a promising direction for future cancer treatments.