In Situ Nanofiber Patch Boosts Postoperative Hepatocellular Carcinoma Immune Activation by Trimodal Combination Therapy.

Poor clinical efficacy associated with postoperative hepatocellular carcinoma (HCC) often results from recurrence and metastasis. Hence, research has focused on establishing an effective multimodal therapy. However, complex combinations of active ingredients require multiple functions in therapeutic systems. Herein, a portable nanofiber patch composing germanium phosphorus (GeP) and anlotinib (AL) was designed to form a versatile platform for molecularly targeted photothermal-immune checkpoint blockade (ICB) trimodal combination therapy. The patches possess hydrophilic, satisfactory mechanical, and excellent photothermal conversion properties. Moreover, they achieve a penetrating and sustained drug release. The near-infrared light-assisted GeP-induced temperature increase regulates AL release, downregulating the expression of vascular-related factor receptors, triggering immunogenic cell death of tumor cells, and inducing dendritic cell maturation. Simultaneously, ICB therapy (programmed cell death ligand 1, PD-L1) was introduced to improve treatment outcomes. Notably, this trimodal combination therapy significantly inhibits vascular hypergrowth, enhances effector T-cell infiltration, and sensitizes the PD-L1 antibody response, boosting immunotherapy to suppress residual HCC recurrence and metastasis. Further validation of the genome sequencing results revealed cell pathways related primarily to regulatory immune effects. This study demonstrates the use of an effective and practical nanofiber patch to improve multimodal therapy of postoperative HCC, with high clinical translation value.

Cascade-Reaction-Based Nanodrug for Combined Chemo/Starvation/Chemodynamic Therapy against Multidrug-Resistant Tumors.

We report a chemo/starvation/chemodynamic trimodal combination therapy to combat multidrug-resistant (MDR) tumors by developing a ferrocene-containing nanovesicle (FcNV), which encapsulates glucose oxidase (GOx) in the hydrophilic core and coordinates cisplatin (Pt) in the hydrophobic layer (GOx&Pt@FcNV). Contrasting with other reported multimodal combination therapies, the new nanodrug (GOx&Pt@FcNV) relies on cascade reactions to drastically increase the overall effectiveness against MDR tumors. Specifically, Pt blocks deoxyribonucleic acid replication and activates hydrogen peroxide (H2O2) generation for chemotherapy; GOx consumes glucose to produce H2O2 and gluconic acid for starvation therapy; and all H2O2 products are catalyzed by ferrous ions decomposed from ferrocene to generate the highly toxic hydroxyl radicals (•OH) for chemodynamic therapy. The in vitro studies reveal that GOx&Pt@FcNV exhibits a highly efficient killing effect against various MDR tumor cells. The in vivo studies of double-tumor-bearing nude mice demonstrate that the tumor inhibitory rates (TIRs) of GOx&Pt@FcNV against cisplatin-resistant A549/DDP are 8.1 times and 3.3 times higher than those of Pt and Pt@FcNV, respectively; they are also 8.6 times and 4.3 times higher than Pt and Pt@FcNV against adriamycin-resistant MCF-7/ADR, respectively. This nanodrug with endogenous stimuli-activated cascade reactions offers a reference for the design of effective trimodal combination therapies to combat MDR tumors.