The zeta potential of nanoparticles impacts their distribution and metabolism in the body as well as their interaction with medications of varying charges, hence altering therapeutic efficacy and safety. In this paper, the external charges of liposomes were regulated by utilizing a simple and economical method based on competition for protons of cationic chitosan (CS) and anion hyaluronic acid (HA). The charge regulation of a liposomal membrane is generally accomplished by adjusting the ratio of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS), the stability of which was maintained by the coating materials of cationic chitosan (CS) or anion hyaluronic acid (HA). A series of nanoparticles could respond to pH-stimulation with adjustable surface charge. Moreover, the sizes of liposomes coated with CS and HA remain within a narrow range. In vitro cytotoxicity tests revealed that the nanocarriers were safe, and the nanoparticles containing antitumor medicines were efficient in tumor therapy. Considering liposomes with different external surface charges could be aimed at diverse therapy purposes. The strategies for regulating liposomal surface charges with high encapsulation rates and certain release cycles reported here could provide a versatile platform as carriers for the delivery of drugs and other macromolecules into human bodies.