Tumor Microenvironment ROS/pH Cascade-Responsive Supramolecular Nanoplatform with ROS Regeneration Property for Enhanced Hepatocellular Carcinoma Therapy

• DOI: 10.1021/acsami.3c16022
• Publication Date: 2024-02-06T02:44:42Z
• Authors: Jinfeng Shi; Yehui Wang; Yihan Wu; Jingjing Li; Chaomei Fu; Yi Li; Xingliang Xie; Xiaohong Fan; Yichen Hu; Chuan Hu; Jinming Zhang
• Keywords: Internalization

The low targeted drug delivery efficiency, including poor tumor accumulation and penetration uncontrolled release, leads to the failure of cancer therapy. Herein, a multifunctional supramolecular nanoplatform loading triptolide (TPL/PBAETK@GA NPs) was fabricated via host–guest interaction between glycyrrhetinic-acid-modified poly(ethylene glycol)-adamantanecarboxylic acid moiety reactive oxygen species (ROS)/pH cascade-responsive copolymer poly(β-amino esters)-thioketal (TK)-β-cyclodextrin. TPL/PBAETK@GA NPs could accumulate in hepatocellular carcinoma (HCC) tissue effectively, mediated by nanoscale advantage GA' recognition specific receptors. elevated concentration ROS microenvironment (TME) quickly breaks TK linkages, causing detachment shell (cyclodextrin) CD layer. Then, accompanying negative-to-positive charge-reversal realized PBAE protonation under slightly acidic TME, significantly enhancing NPs' cellular internalization. Remarkably, pH-responsive endo/lysosome escape core triggered intracellular TPL burst promoting cell apoptosis, autophagy, generation, leading self-amplification TME. Afterward, positive-feedback loop generated further promote size-shrinkage NPs. Both vitro vivo tests verified that produced satisfactory anti-HCC therapy outcome. Collectively, this study offers potential appealing paradigm enhance TPL-based HCC outcomes multifunctionalized nanodrugs.