The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

Treatments for lung adenocarcinoma, a type of non-small-cell lung cancer that accounts for about 40% of all lung cancers, are generally administered intravenously, thus causing systemic side effects and poor pulmonary delivery. Inhalation therapy has been investigated to overcome these limitations; however, it shows limited delivery of drugs to the distal lung region, rapid clearance by alveolar macrophages, and immune responses due to synthetic materials. In this study, we developed inhalable nanotherapeutics to treat lung adenocarcinoma using exogenous pulmonary surfactant (PS) that are lipid-based, clinically used, and easy to fuse with the endogenous PS layer in the alveolar space. We prepared PS-based nanovesicles (PSNVs) using the thin-film hydration method followed by extrusion. PSNVs interacted selectively with alveolar type II cell-derived adenocarcinoma cells in vitro and retained long in the alveolar space of mice after inhalation, presumably due to the incorporated PS proteins. Furthermore, inhalation treatments of paclitaxel-loaded PSNVs significantly inhibited the tumor growth in the lungs of the orthotopic lung cancer mouse model established by intratracheally injection of A549 cells into nude mice, compared with free paclitaxel and paclitaxel-loaded synthetic NVs. These results suggest that the use of PSNVs for inhalation delivery of a wide range of therapeutic agents has great potential for the treatment of various lung diseases, including lung adenocarcinoma.