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

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.

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.

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.

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.