Customized Nanofibers with Lung-Targeting and -Retention Properties for Treating Isolated Triple-Negative Breast Cancer Pulmonary Metastases

Systemic chemotherapy remains the primary treatment for metastatic triple-negative breast cancer, but its effectiveness is limited, and clinical outcomes are poor. FDA-approved molecular targeted therapies and immunotherapies address only a subset of breast cancer patients, overlooking tumor heterogeneity and complexity. Additionally, these therapies suffer from short local retention times and subtherapeutic concentrations at tumor sites. Here, we present peptide-based nanofibers (pNFP6) with significant lung targeting and retention properties for treating pulmonary metastases. The nanofibers display a 2D single-layer structure with a high aspect ratio (5 nm in width and 8 μm in length), promoting lung affinity. Shortly after systemic administration, 75% of the total pNFP6 reached the lungs, minimizing uptake by other organs and reducing off-target accumulations. Interactions between multiple nanofibers formed larger interfibril networks, enhancing local accumulation and retention. Light sheet fluorescence microscopy imaging revealed that pNFP6, when used as a drug (doxorubicin) carrier, macroscopically improved delivery to diseased lungs and offered sustained treatment. At a microscopic level, the drug-loaded pNFP6 (aldox-pNFP6) interacted with the cell surface and released the drug in close proximity. Compared to the clinically used free drug and liposomal formulation (Doxil), aldox-pNFP6 exhibited superior therapeutic outcomes with reduced toxicities. Overall, this approach provides full lung coverage, enabling continuous, localized release of a broad spectrum of antitumor activity.