Activated hepatic stellate cell membrane-camouflaged nanomedicine enables targeted HDAC6 inhibition for liver fibrosis therapy.

Liver fibrosis is a common outcome of chronic liver injury and can progress to cirrhosis, yet effective anti-fibrotic therapies remain limited. Here, we identify histone deacetylase 6 (HDAC6) as the most consistently upregulated zinc-dependent HDAC in fibrotic livers and activated hepatic stellate cells (HSCs). However, systemic HDAC6 inhibition may be constrained by inefficient delivery to fibrogenic HSCs and increased off-target exposure. To enable selective HDAC6 inhibition in activated HSCs, we developed an activated HSC membrane-camouflaged PLGA nanomedicine (PLGA-Ric@HSCM) loaded with the HDAC6 inhibitor ricolinostat (Ric). Membrane cloaking preserves key adhesion and recognition proteins, promotes homotypic uptake by HSCs, and reduces macrophage sequestration in vivo. PLGA-Ric@HSCM dampened profibrotic transcriptional programs by restoring microtubule acetylation and suppressing both the canonical TGFβ/Smad2/3 pathway and the p38/c-JUN/ATF2 axis. Compared to PLGA-Ric, PLGA-Ric@HSCM shows a more pronounced reduction in fibrosis burden and improved hepatic pathology across etiologically distinct models. Together, PLGA-Ric@HSCM provides a biomimetic, HSC-targeted strategy to reprogram acetylation homeostasis via HDAC6 inhibition and consequently mitigate liver fibrogenesis.