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Simple Summary Only 13 to 50% of patients with metastatic melanoma respond to new commercialized therapies. The reason why the same chemotherapeutic treatments yield different responses in patients can be attributed to the degree of multidrug resistance (MDR) developed by the host tumor cells. For instance, the glycolytic metabolism of cancer cells enhances the intratumoral accumulation of lactic acid, decreases intratumoral pH and potentiates MDR. Lipid nanoparticles (LNC) have been widely exploited as carriers of MDR reversing molecules. In this study, we proposed to modify LNC with novel copolymers to impart stealth properties and to improve tumor cell entry. Modified-LNC showed in vitro pH-responsive properties characterized by an enhanced cellular uptake under acidic conditions. Moreover, surface modification led to an increased biological effect by protecting the nanocarrier from opsonization by complement activation. These data suggest that pH-sensitive LNC are promising nanocarriers to target metastatic melanoma. Abstract Despite significant advances in melanoma therapy, low response rates and multidrug resistance (MDR) have been described, reducing the anticancer efficacy of the administered molecules. Among the causes to explain these resistances, the decreased intratumoral pH is known to potentiate MDR and to reduce the sensitivity to anticancer molecules. Nanomedicines have been widely exploited as the carriers of MDR reversing molecules. Lipid nanocapsules (LNC) are nanoparticles that have already demonstrated their ability to improve cancer treatment. Here, LNC were modified with novel copolymers that combine N-vinylpyrrolidone (NVP) to impart stealth properties and vinyl imidazole (Vim), providing pH-responsive ability to address classical chemoresistance by improving tumor cell entry. These copolymers could be post-inserted at the LNC surface, leading to the property of going from neutral charge under physiological pH to positive charge under acidic conditions. LNC modified with polymer P5 (C18H37-P(NVP21-co-Vim15)) showed in vitro pH-responsive properties characterized by an enhanced cellular uptake under acidic conditions. Moreover, P5 surface modification led to an increased biological effect by protecting the nanocarrier from opsonization by complement activation. These data suggest that pH-sensitive LNC responds to what is expected from a promising nanocarrier to target metastatic melanoma.