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However, current existing fusion\u2010regulating strategies often suffer from insensitivity and unidirectional control, leading to suboptimal antitumor effects and potential safety risks. Here, we designed a pyridinium betaine\u2010capped lipid, 2\u2010(4\u2010((2,3\u2010di(stearoyloxy)propyl)carbamoyl)pyridin\u20101\u2010ium\u20101\u2010yl)acetate (DSPCPA)), as a pH\u2010responsive regulator to precisely manipulate the membrane\u2010fusion behavior of fusogenic liposomes. Incorporating DSPCPA, we optimized a formulation of\n                    <jats:bold>s<\/jats:bold>\n                    elf\u2010a\n                    <jats:bold>d<\/jats:bold>\n                    aptive,\n                    <jats:bold>en<\/jats:bold>\n                    vironment\u2010responsive\n                    <jats:bold>fu<\/jats:bold>\n                    sogenic\n                    <jats:bold>l<\/jats:bold>\n                    iposome (SENDFUL) capable of rapidly and reversibly switching membrane\u2010fusion activity responding acidic tumor microenvironments. At physiological pH, SENDFUL remains negatively\u2010charged due to the zwitterionic nature of DSPCPA, undergoing in a non\u2010fusogenic state. In acidic tumor regions (pH 6.5), protonation of DSPCPA rapidly converts surface charge to positive, triggering tumor\u2010specific fusion via strengthened electrostatic interactions with cellular membranes. This reversible transition highly confines lysosome\u2010bypassing cytosolic delivery to tumors, minimizing systemic toxicity. We utilized SENDFUL to construct a nanoagonist for the stimulator of interferon genes (STING) pathway, which elicited potent antitumor immunity with negligible toxicity in vitro and in vivo. Thus, SENDFUL represents an advanced strategy for spatially precise regulation of liposomal membrane fusion, providing a safe and efficient platform for tumor\u2010specific intracellular drug delivery.\n                  <\/jats:p>","DOI":"10.1002\/anie.202522025","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T06:34:48Z","timestamp":1770964488000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lipid Modified with Pyridinium Betaine Manipulates Liposomal Membrane Fusion Behavior for Spatially Confined Cytoplasmic Delivery"],"prefix":"10.1002","volume":"65","author":[{"given":"Huijuan","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Chemistry South China Normal University  Guangzhou 510006 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