ROS-Responsive Silica Cross-Linked Micelle Drug Delivery System for Myocardial Ischemia-Reperfusion Injury Therapy

Abstract Myocardial ischemia-reperfusion injury (MIRI) remains a formidable clinical and therapeutic obstacle, which is primarily driven by excessive oxidative stress, calcium overload, and persistent inflammatory cascades. Natural polyphenols, renowned for their superior antioxidant and anti-inflammatory bioactivities, are regarded as high-potency therapeutic candidates for MIRI alleviation. To achieve targeted and efficient polyphenol delivery for MIRI treatment, a reactive oxygen species (ROS)-responsive silica cross-linked micelle nanocarrier (TK-SCLM) was fabricated in this work for the encapsulation of four typical polyphenolic components, including chlorogenic acid, rutin, quercetin, and 6,7-dihydroxycoumarin. Benefiting from the enhanced permeability and retention effect, the engineered TK-SCLM nanosystem enables precise accumulation and targeted therapy toward ischemic myocardial tissues. In vitro antioxidant evaluation verified that quercetin possesses the optimal free radical-scavenging capability among the four polyphenols, which can efficiently protect cardiomyocytes from oxidative injury. Furthermore, in vivo therapeutic assessments on rat MIRI models confirmed that quercetin-loaded TK-SCLMs (Q@TK-SCLMs) can markedly alleviate myocardial oxidative damage, reduce infarct size, and maintain stable cardiac physiological function. This work develops a versatile ROS-responsive silica cross-linked micelle nano-platform, providing an innovative material-based strategy for targeted MIRI therapy.