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Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) (PBFSU) polyesters, comprising an 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer new lysosome acidifying nanoparticles (NPs). Notably, TFSA NPs, which composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying property. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase (V-ATPase) subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets and INS-1 β-cells under lipotoxic condition. Treatment of TFSA NPs counteracts lipotoxicity in INS-1 β-cells by restoring lysosomal acidification, autophagic function, and mitochondrial activity, along with promoting glucose-stimulated insulin secretion. Administration of TFSA NPs to high-fat diet T2D mice improves glucose clearance and reduces insulin resistance. These findings highlight the therapeutic potential of lysosome acidifying TFSA NPs for T2D.

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