Nanoparticle-mediated dual targeting of stromal and immune components to overcome fibrotic and immunosuppressive barriers in hepatocellular carcinoma.

Cancer-associated fibroblasts (CAFs) are key drivers of hepatocellular carcinoma (HCC) through their promotion of fibrosis and immune suppression activity. To overcome this stroma-immune barrier, we developed D/F@MRL, a stroma-immune co-targeting nanoplatform that enables the spatiotemporal coordination of CAF reprogramming and immune activation. In D/F@MRL, MMP-2-responsive hybrid liposomes (MRL) was employed to co-load digoxin (Dig) and PD-L1-degrading nanofibers (NFs). Upon encountering the MMP-2-enriched HCC stroma, D/F@MRL undergoes enzymatic cleavage, thereby enabling the targeted release of Dig and NFs within the HCC microenvironment. Mechanistically, Dig inhibits the phosphorylation of SMAD3 in CAFs, while PD-L1 degradation destabilizes the TGFβ receptor, synergistically silencing TGF-β/Smad signaling to reprogram CAFs. This combination not only disrupts the fibrotic barrier but also creates a feed-forward loop that further enhances drug penetration, while reinforcing the immune activation driven by Dig-induced immunogenic cell death (ICD) and PD-L1 degradation. In the humanized immune PDX model, D/F@MRL successfully reprogrammed CAFs and robustly remodeled the stromal and immune microenvironments without causing systemic toxicity, highlighting its promising potential for clinical translation. By integrating CAF reprogramming with ICD and immune checkpoint inhibition, this strategy overcame the limitations of single-target therapies, induced robust immune activation, further provided a clinic-transformative approach for fibrotic malignancies.