Cellular lipid bilayer in low extracellular pH

The cellular lipid bilayer in low extracellular pH is a specialized physiological target characterized by the acidic microenvironment (pHe 6.0–7.0) typical of solid tumors, ischemic tissues, and sites of chronic inflammation [1][2]. Unlike traditional protein receptors, this target relies on the physical-chemical properties of the membrane and the surrounding environment, specifically the increased concentration of protons [3]. This acidity triggers the protonation of specific residues in pH-sensitive molecules, such as pH-Low Insertion Peptides (pHLIPs), which then transition from a soluble state to a transmembrane alpha-helix that inserts into the lipid bilayer [4]. This mechanism allows for the highly selective delivery of imaging agents, chemotherapeutics, or molecular probes to diseased cells while sparing healthy tissues at physiological pH (7.4) [5]. The target is particularly valuable in oncology because it exploits the universal Warburg effect (aerobic glycolysis), making it less susceptible to the genetic heterogeneity and resistance mechanisms that often plague protein-targeted therapies [6]. Furthermore, the acidic lipid bilayer serves as a platform for smart drug delivery systems, including pH-responsive liposomes and nanoparticles that release their cargo upon sensing the acidic gradient [7].

Other names

Acidic cell membraneLow-pH cell surfaceTumor acidic microenvironment membraneAcidic lipid bilayerpHe-sensitive membrane

Protonation-triggered transmembrane insertion and cargo delivery