Mitochondrial targeting of anticancer drugs can effectively eradicate chemotherapy-refractory cells through different mechanisms. This work presents the rational designing of mitochondria-targeted core-shell polymeric nanoparticles (NPs) for efficient delivery of doxorubicin (DOX) to the hepatic carcinoma mitochondria. DOX was electrostatically nano-complexed with sodium alginate (SAL) then coated with mitotropic triphenylphosphonium-grafted chitosan (TPP+-g-CS) nanoshell. Polyvinyl alcohol (PVA) was co-solubilized into the TPP+-g-CS solution to enhance the stability of the developed NPs. The optimum NPs formula is composed of TPP+-g-CS (0.05% w/v) coating a DOX-SAL core complex (0.05% w/v), with 0.2% PVA relative to CS (w/w). The optimum NPs attained an entrapment efficiency of 63.33 ± 10.18%; exhibited a spherical shape with particle size of 70-110 nm and a positive surface charge which enhances mitochondrial uptake. FTIR and DSC studies results were indicative of an efficacious poly-complexation. In vitro biological experiments proved that the developed mitotropic NPs exhibited a significantly lower IC50, effectively induced apoptotic cell death and cell cycle arrest. Moreover, the in vivo studies demonstrated an enhanced antitumor bioactivity for the mitotropic NPs along with a reduced biological toxicity profile. In conclusion, this study proposes a promising nanocarrier system for the efficient targeting of DOX to the mitochondria of hepatic tumors.