Remodeling the Tumor Microenvironment via Metal-Phenolic Network-Coated Poly(lactic acid-<i>co</i>-glycolic acid) Nanoparticles for Inducing Multimodal Combination Therapy in Non-Small Cell Lung Cancer

The treatment of non-small cell lung cancer (NSCLC) primarily relies on chemotherapy following surgical intervention. However, many late-stage NSCLC patients exhibit drug resistance and experience significant side effects from current chemotherapy agents, ultimately leading to disease progression. Consequently, the development of strategies to enhance efficacy while minimizing side effects through multimodal synergistic treatment technologies remains challenging. Here, we prepared a stable multifunctional nanocomplex, PLGA@DTX@Fe³⁺-TA/GO_X (PDFTG), which utilizes poly(lactic acid-<i>co</i>-glycolic acid) (PLGA) nanoparticles to encapsulate docetaxel (DTX) as the core component, while a Fe³⁺-tannic acid (TA) nanonetwork serves as the outer coating. Additionally, interactions between polyphenols and proteins facilitate the loading of glucose oxidase (GO_X). After intravenous injection, PDFTG selectively accumulates in the tumor region, subsequently releasing Fe³⁺, TA, DTX, and GO_X, thereby remodeling the tumor microenvironment. Following this process, Fe³⁺ is reduced to Fe²⁺ by TA, leading to mitochondrial damage in cancer cells and resulting in an increase in O₂ content. This increase promotes the GO_X-catalyzed glucose oxidation reaction that generates gluconic acid and H₂O₂, initiating starvation therapy. The gluconic acid enhances the acidity of the microenvironment, further promoting the release of PDFTG nanoparticles and enhancing the accumulation of H₂O₂ within the cell. The accumulated H₂O₂ reacts with Fe²⁺ in a strongly acidic environment, leading to the of hydroxyl free radicals that initiate chemical dynamic therapy (CDT). Moreover, mitochondrial damage results in a reduction of adenosine triphosphate levels, which decreases the expression of P-glycoprotein, thereby reversing DTX resistance and producing potent multimodal synergistic antitumor effects. Multimode treatment strategies for reshaping the tumor microenvironment offer an approach with significant clinical application potential for the efficient treatment of NSCLC.