PLGA-based nanoparticles are the most studied for cancer therapy. Insufficient stability and sustained drug release, however, often lead to reduced targetability and antitumor efficacy . In this work, we report on cRGD-installed reduction-responsive cross-linked nanotherapeutics based on a star PLGA-lipoic acid conjugate (cRGD-sPLGA XNPs) for potent and targeted chemotherapy of B16F10 melanoma in mice. cRGD-sPLGA XNPs exhibited nearly quantitative encapsulation of doxorubicin (DOX), giving DOX-cRGD-sPLGA XNPs with 13.2 wt % DOX and a small size of 91.0 ± 0.6 nm. DOX-cRGD-sPLGA XNPs with a cRGD surface density of 48% exhibited the best cellular uptake in αβ overexpressing B16F10 cells and delivered DOX into the cell nuclei after 6 h of incubation, in contrast to nontargeted DOX-sPLGA XNPs that delivered DOX mainly in the cytoplasm. Cell viability experiments showed that DOX-cRGD-sPLGA XNPs had about 2-fold better inhibitory activity in B16F10 cells than nontargeted DOX-sPLGA XNPs. Interestingly, DOX-cRGD-sPLGA XNPs achieved a great melanoma accumulation of 10.96% ID/g and significantly better suppression of B16F10 melanoma than DOX-sPLGA XNPs and Lipo-DOX. DOX-cRGD-sPLGA XNPs brought about marked improvement of the survival rate of B16F10 melanoma-bearing mice at 20 mg of DOX equiv/kg. Smart nanotherapeutics based on the star PLGA-lipoic acid conjugate have emerged as an appealing nanoplatform for targeted tumor therapy.