Biomimetic PLGA nanoparticles-mediated low-intensity pulsed ultrasound-triggered targeted release of C646 for esophageal cancer therapy.
Abstract
Esophageal squamous cell carcinoma (ESCC) is associated with high morbidity and poor clinical prognosis among the Chinese population. Conventional chemoradiotherapy is hampered by severe systemic toxic effects and inadequate tumor-targeting performance. EP300 represents a promising epigenetic therapeutic target for ESCC. Nevertheless, the small-molecule EP300 inhibitor C646 suffers from low target selectivity and substantial off-target toxicity. Herein, we constructed homotypic tumor-cell-membrane-coated, C646-loaded PLGA nanoparticles (C646/PLGA@CM NPs). This nanosystem integrates biomimetic homologous targeting, immune evasion capability, and low intensity pulsed ultrasound (LIPUS, US)-triggered on-demand release for combinatorial therapy against ESCC. Physicochemical characterizations confirmed successful membrane coating, satisfactory colloidal stability, and US-triggered drug-release profiles. Cellular assays demonstrated that C646/PLGA@CM NPs achieve efficient homologous uptake in tumor cells and evade phagocytosis by macrophages. Quantitative analysis using SynergyFinder confirmed strong synergistic antitumor effects of the nanoparticles combined with US. In vitro assays showed that C646/PLGA@CM combined with US markedly suppressed the proliferation and migration of KYSE-140 cells by inducing G2/M-phase cell-cycle arrest and reversing epithelial-mesenchymal transition (EMT). Furthermore, results from ESCC subcutaneous xenograft mouse models revealed that C646/PLGA@CM combined with US exerted potent in-vivo antitumor efficacy with satisfactory biosafety. Transcriptomic profiling together with qRT-PCR assays indicated that the antitumor mechanism involves EP300-inhibition-mediated activation of the p53/FoxO pathway, alongside dysregulation of tumor-suppressive and oncogenic miRNAs. Collectively, this CM-coated nanoplatform combined with US offers a feasible precision-targeted therapeutic strategy for ESCC.