Progress in Drug Delivery by Stimulus-responsive Liposomes in the Acidic Environment of Tumors

Abstract

The tumor-associated microenvironment (TAM) being acidic is one of the significant characteristics of solid tumors. This affects the cellular uptake and activity of drugs, promotes the formation of drug resistance and invasiveness, and limits the therapeutic efficacy. Stimuli-responsive liposomes, compared with traditional drug carriers, have higher precision, utilization rate, and potential for combination therapy. They remain stable under physiological pH conditions but undergo structural changes or disintegrate in acidic environments, thereby achieving targeted drug release and enrichment. This offers broad application prospects in precise tumor treatment. The research on the acidic characteristics of the TAM has driven the development of various types of stimulus-responsive liposomes. pH-sensitive liposomes can achieve precise drug release in acidic environments; redox-type liposomes enhance drug release by taking advantage of the high ROS levels in tumors; enzyme-responsive liposomes rely on tumor-specific enzymes to trigger the dissociation of the structure. All three significantly improve the efficiency of drug delivery and therapeutic effects, providing multi-dimensional strategies and potential advantages for the design of anti-tumor nanomedicines. This review aims to systematically summarize the design strategies and application progress of stimulus-responsive liposomes in acidic tumor microenvironments, evaluate their in vitro and in vivo performance and clinical translational potential, and discuss the main challenges and corresponding solutions, with the expectation of promoting the clinical application of precise tumor treatment.