Engineered desialylated platelet membrane camouflaged liposomes for the regulation of kupffer cells and hepatic stellate cells in treatment of liver fibrosis

The intercellular crosstalk and reciprocal activation between Kupffer cells (KCs) and hepatic stellate cells (HSCs) are critical drivers of liver fibrosis progression. Nonetheless, the co-regulation of KCs and HSCs is hindered by their distinct anatomical locations and the pathological barriers driven by liver sinusoidal capillarization and aberrant extracellular matrix (ECM) deposition. To address this challenge, we developed a sequential drug delivery nanoplatform (AP13-Cur@DPMLip) which comprises curcumin-loaded liposomes (Cur@Lip) and a desialylated platelet membrane (DPM) camouflage featuring matrix metalloprotease 9 (MMP-9)-responsive release of a platelet-derived growth factor receptor (PDGFR) antagonistic peptide (termed AP13). This biomimetic system exhibits liver-specific distribution and targets KCs via DPM-derived homing capability, followed by Cur-mediated modulation of pro-inflammatory KC phenotypes. Concurrently, AP13 is rapidly released in response to MMP-9 secreted by KCs, subsequently penetrating the sinusoidal capillarization-induced decrescent fenestrae and dense ECM, and inhibited the activation of HSCs. Additionally, rats with liver fibrosis exhibit inflammation remission, collagen reduction and negligible side effects after AP13-Cur@DPMLip treatment. Our findings propose a new strategy for the regulation of KCs and HSCs and highlight the potential of their synergistic deactivation in the treatment of liver fibrosis.