Exploring structure influence of mPEG-PLGA nanocarriers on their interaction with physiopathological barriers in the lung and anti-lung cancer effect

Inhalable nanomedicines hold great promise for lung cancer therapy, yet how carrier structure dictates their pulmonary fate remains insufficiently understood. From a fundamental research perspective, this study aims to investigate how structurally distinct nanocarriers interact with physiopathological barriers in the lungs, with the goal of providing a theoretical foundation for inhalation therapy. By keeping the composition and material properties of the carriers comparable, different structured paclitaxel-loaded mPEG-PLGA nanocarriers, including nanoparticles, polymersomes, and micelles, were prepared by selecting different hydrophobic chain mPEG-PLGA diblock copolymers. It was found that nanoparticles with solid structure showed the slowest drug release rate, and the strongest cellular uptake but are difficult to overcome the barriers in the lung mucus with limited tumor permeability. In contrast, polymersomes with a less rigid structure have a better capacity to overcome the mucus and tumor barrier and therefore have the best lung retention but the weakest cellular uptake. The micelles with the smallest particle size have the strongest tumor permeability and the most prominent lymphatic distribution but the fastest drug release rate thus the most prominent extrapulmonary distribution. Remarkably, despite these divergent behaviors, their overall antitumor efficacy converged, revealing a compensatory balance among structural advantages and limitations. By bridging mechanistic insights with therapeutic outcomes, this study establishes a structure–function framework for pulmonary delivery. These findings advance fundamental understanding of how nanocarrier structure shapes drug fate and efficacy and provide generalizable principles to guide the rational design and clinical translation of inhalable nanomedicines for lung cancer and other pulmonary diseases.