Polydopamine (PDA) is a polymer obtained from the self-polymerization of dopamine monomers; during the synthesis process, spherical nanoparticles are formed (PDA NPs), presenting several interesting properties such as high drug encapsulation capacity, easy and versatile surface modification, ability to convert near-infrared radiation (NIR) into heat, and strong antioxidant properties. In this work, PDA NPs have been proposed as an anti-cancer tool through the combination of NIR-mediated hyperthermia loading with a chemotherapeutic agent, sorafenib (SRF), specifically effective on liver cancer. Cell membranes isolated from hepatocarcinoma cancer cells (HepG2) have been exploited for the coating of the nanoparticles (thus obtaining CM-SRF-PDA NPs), in order to achieve homotypic targeting. The selective targeting capacity, photothermal, and chemotherapeutic activity of CM-SRF-PDA NPs have been evaluated on cell cultures in static and dynamic conditions, besides on 3D culture models. Eventually, the therapeutic effectiveness of the proposed approach has also been tested ex-ovo on a HepG2 spheroids-grafted chorioallantoic membrane model of quail embryos. This comprehensive investigation, supported by proteomic analysis, strongly suggest the developed nanoplatform for further pre-clinical investigations in the treatment of liver cancer.