Self-healing hydrogel loaded with M2pep-modified recombinant apoferritin enhanced chemotherapy in hepatocellular carcinoma via reprogramming tumor-associated macrophage

Chemotherapy plays an important role in the clinical systemic management of advanced hepatocellular carcinoma (HCC). However, the efficacy of chemotherapy is remarkably suppressed by the tumor microenvironment. After observing the prevalent M2-tumor associated macrophages (TAMs) in clinical HCC specimen, we developed a dual protein drug delivery system, namely, genetically engineered M2 macrophage targeting peptide (M2pep) modified recombinant apoferritin (HFn) for the delivery of "old drug" chloroquine (CQ), and bovine serum albumin (BSA) for the delivery of PTX for the synergistic treatment of HCC. To avoid additional efficacy limitations caused by systemic exposure, BSA@PTX and M2-HFn@CQ were incorporated into a self-healing hydrogel (COT@BP/M2HC) composed of carboxymethyl chitosan, oxidized sodium alginate and tannic acid. The experimental results demonstrated this COT@BP/M2HC hydrogel had good biocompatibility and biodegradability, adhesion, injectability and self-healing properties. It was further confirmed that a single peritumoral injection of COT@BP/M2HC successfully promoted the polarization of M2 TAMs to M1 TAMs, and the M1/M2 ratio increased by 4.63 times compared with the BSA@PTX group, thereby achieving 74.7 % tumor growth inhibition in HCC tumor-bearing mouse models. These findings revealed a potential TAM polarizing effect of CQ and provided a reliable combination strategy for improving HCC chemotherapy efficacy.