Inhalable polyphenolic-based nanoparticles for localized lung cancer treatment.

Abstract

e20758 Background: Lung cancer remains a leading cause of cancer-related morbidity and mortality worldwide. Although conventional chemotherapy is a mainstay of treatment, its clinical utility is often limited by systemic toxicity, poor bioavailability at the tumor site, and off-target effects. Inhalation-based drug delivery using nanocarriers has emerged as a promising strategy to achieve localized lung targeting, bypass first-pass metabolism, and enhance therapeutic efficacy while minimizing systemic exposure. In this study, we report a facile inhalable, tannic acid–based nanoparticles (GA@TANPs) as a polyphenolic nanoplatform for localized lung cancer therapy. Methods: Gambogic acid (GA)–loaded CTA nanoparticles (GA@TANPs) were synthesized via a cross-linking approach and comprehensively characterized for physicochemical properties, including particle size, morphology, thermal behavior, chemical composition, and drug-loading efficiency using DLS, FT-IR, DSC, SEM/TEM, and TGA. Cellular uptake and intracellular trafficking were evaluated in A549 and NCI-H1299 lung cancer cells using fluorescence microscopy and flow cytometry. The therapeutic potential of GA@TANPs was assessed through in vitro cytotoxicity (CCK-8), mucoadhesion, mucopenetration, Boyden chamber migration, spheroid penetration, and apoptosis assays. Results: The optimized GA@TANPs exhibited a spherical morphology with a mean particle size below 200 nm and a mildly negative surface charge (−7.1 ± 0.5 mV), suitable for deep lung deposition. The nanoparticles demonstrated sustained drug release, enhanced mucus penetration, and improved tumor spheroid infiltration, closely mimicking in vivo tumor conditions. Cellular uptake studies confirmed significantly higher intracellular accumulation of GA@TANPs compared to free GA, with evidence of efficient endosomal escape. Functionally, GA@TANPs showed superior anticancer activity, including reduced cell viability, inhibited migration, and increased apoptosis in both lung cancer cell lines. Conclusions: These findings highlight the potential of nebulization-based inhalable GA@TANPs formulations as an effective localized drug delivery system for lung cancer therapy.