A layered target-release nanoparticle system for normalizing the lung cancer microenvironment and enhancing antitumor effect.

BACKGROUND: Abnormal tumor vasculature and dense collagen fiber networks contribute to elevated interstitial pressure in solid tumors, compressing blood vessels and impairing the delivery of nanoparticle (NP)-based therapeutics. Promoting normalization of the tumor microenvironment is a promising strategy for enhancing drug penetration. This study aimed to develop a pH-responsive bilayer nanoplatform capable of sequentially delivering a microenvironment modulator and a targeted chemotherapeutic agent for improved efficacy against lung cancer. METHODS: We designed a bilayer lipid NP system with an inner core of triptolide (TPL) encapsulated in folic acid-modified chitosan for tumor cell targeting. The outer layer was composed of pH-sensitive dioleoylphosphatidylethanolamine (DOPE) lipids, co-encapsulated ligustrazine (LT), and TPL-loaded nanoparticles (TPL-NPs) to form LT-co-encapsulated TPL-NPs (LT@TPL-NPs). NP characterization, pH-responsive release profiling, and in vitro cellular uptake assays were performed. All animal experiments were conducted following institutional ethical guidelines. RESULTS: In the acidic tumor microenvironment, LT@TPL-NPs triggered the sequential release of LT followed by TPL-NPs. LT promoted the normalization of the tumor microenvironment, characterized by reduced interstitial pressure and enhanced NP penetration depth. The released TPL-NPs, modified with folic acid and carrying a positive surface charge, demonstrated efficient cellular uptake and intracellular drug delivery in lung cancer cell models. CONCLUSIONS: This pH-responsive bilayer nanoplatform enables spatiotemporally controlled release of a microenvironment-modulating agent and a targeted chemotherapeutic, achieving synergistic effects of physical barrier remodeling and tumor cell cytotoxicity. This strategy offers a potential approach to overcoming delivery barriers in solid tumors and should be further evaluated in preclinical models of thoracic malignancy.