A Cascade‐Targeting System Delivering Polyphenol Into the Mitochondria of M1 Macrophages for Inflammatory Bowel Disease Therapy

Precise intervention targeting the mitochondria of macrophages represents a promising therapeutic strategy to address the challenges of limited clinical efficacy and high risk of adverse reactions in current pharmacological treatments for inflammatory bowel disease (IBD). Herein, a cascade-targeting system, namely HP-mExo/TP@Qu (HET@Qu), is rationally designed for the precise delivery of quercetin (Qu, a natural polyphenol with antioxidant and anti-inflammatory properties) to the mitochondria of intestinal M1 macrophages. HET@Qu comprises a CD44-targeting shell (HP-mExo) and a mitochondria-targeting core (TP@Qu), which sequentially enable targeted delivery at the cellular and subcellular levels. Notably, the development of tannic acid (TA)-based mitochondria-targeting micelles (TP@Qu) reported herein demonstrates the feasibility of leveraging natural products for the construction of functional vectors and expands the toolkit of mitochondria-targeted delivery. In animal experiments, HET@Qu demonstrates significant therapeutic efficacy by attenuating inflammatory cascades, restoring the impaired intestinal epithelial barrier, promoting the M2 polarization of macrophages, and rebalancing gut microbiota homeostasis. Collectively, by integrating a CD44-targeting shell and a mitochondria-targeting core, HET@Qu overcomes the last mile challenge of Qu delivery by escorting Qu to critical sites, thereby providing a new choice for the precise treatment of IBD.