Decoupling multicellular activation circuits: MPDA-mediated co-delivery of quercetin/simvastatin for potent hepatic fibrosis reversal

Hepatic fibrosis, primarily driven by the sustained activation of hepatic stellate cells (HSCs), continues to pose a significant global health challenge due to the scarcity of effective therapeutic interventions. Existing single-target approaches are inadequate in addressing the complex multicellular regulatory network within the fibrotic niche, where injured hepatocytes, Kupffer cells (KCs), and capillarized liver sinusoidal endothelial cells (LSECs) collectively perpetuate HSC activation through paracrine signaling mechanisms. To address this challenge, a novel nanoplatform has been developed, comprising a co -delivery system of quercetin (Que) and simvastatin (Sim) within a mesoporous polydopamine (MPDA)-based matrix, designed to achieve the synchronized modulation of multicellular interactions. The MPDA carrier possesses intrinsic liver-targeting and reactive oxygen species (ROS)-scavenging properties, facilitating preferential accumulation in fibrotic lesions and the mitigation of oxidative stress originating from hepatocytes and KCs. In the acidic fibrotic environment, Que and Sim are sustained within the system due to the acid-responsive properties of MPDA. The released Que reprograms pro-inflammatory M1 macrophages into anti-inflammatory M2 phenotypes, while Sim reverses LSEC capillarization, collectively disrupting the microenvironmental factors driving HSC activation. Moreover, all components—MPDA, Que, and Sim—can directly inhibit HSC activation through complementary pathways. This multi-target strategy resulted in a more significant reduction in collagen deposition compared to monotherapies in preclinical models, alongside a notable restoration of liver function. By integrating microenvironmental reprogramming with the interception of multicellular networks, our study establishes a paradigm-shifting nanotherapeutic approach for reversing fibrosis and underscores the potential of engineered multidrug coordination in treating complex stromal diseases.