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Regulation of wound pH from alkaline to acidic is a simple and powerful approach to reduce wound microbial colonization and infection. Here, we present a nanocomposite material possessing intrinsic acidic surface pH as an innovative antimicrobial wound dressing. This material comprises an agarose matrix nanocomposite containing nanoparticles (NPs) of the cesium salt of phosphotungstic heteropolyacid (Cs2.5H0.5PW12O40). Self-supporting films were prepared by a casting method incorporating 5–20 wt % Cs2.5H0.5PW12O40 NPs into the matrix. Films are flexible with tensile strengths between 28.55 and 32.15 MPa and exhibit broad biocidal activity against neutralophilic pathogens, including Gram-positive bacteria, Gram-negative bacteria, yeast, and filamentous fungi. The nano-antimicrobial Cs2.5H0.5PW12O40 functions as an efficient and self-controlled proton delivery agent that lowers the surface pH of the nanocomposites to the range 7.0 > pH ≥ 3.0. Nanocomposite films containing 20 wt % Cs2.5H0.5PW12O40 NPs presented a surface pH of 3.0 and highest antimicrobial activity. Using quantitative reverse transcription polymerase chain reaction, we demonstrated that the antimicrobial mechanism of the nanocomposites is acid-induced because of the transcriptional induction of glutamate-dependent acid resistance genes in Escherichia coli. Additionally, nanocomposite films do not damage skin according to an in vivo rabbit skin model with no derived edema or erythema. The wound care safety of this material is due to low release of heavy metal heteropolyanions ([PW12O40]3–), no nanoparticle leaching, and proton controlled release resulting in nonirritating acid levels for human skin models.

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