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Conventional acyclovir (ACY) therapy is limited by poor bioavailability, rapid clearance, and frequent dosing. We developed an esterified acyclovir prodrug (ACPD) formulated as biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve stability, enable sustained release, and enhance antiviral activity against HSV-1. ACPD was synthesized, ACY-NPs and ACPD-NPs were prepared by nanoprecipitation and single-emulsion solvent evaporation method respectively. Optimized NPs measured 200\u2013300\u00a0nm with polydispersity indices of 0.23\u20130.47 and zeta potentials of \u2212 27 to \u2212 29\u00a0mV. ACPD-NPs provided sustained release for 28\u00a0days. Cytotoxicity in Vero cells yielded CC50 values of 960\u00a0\u00b5M (ACY-NPs) and 1000\u00a0\u00b5M (ACPD-NPs). In HSV-1-infected Vero cells, ACY-NPs exhibited greater antiviral efficacy than free ACY, whereas ACPD and ACPD-NPs showed limited plaque reduction because the tested\n                    <jats:italic>in vitro<\/jats:italic>\n                    media lacked esterase to convert ACPD to ACY. When tested with esterase, cleavage was confirmed by RP-HPLC. Evaluation of ACPD-NPs therapeutic efficacy should be further validated in ocular tissues and in an\n                    <jats:italic>in vivo<\/jats:italic>\n                    ocular model, where esterase enzymes are present. Since corneal tissues contain esterase, its activation may improve ACPD efficacy in\n                    <jats:italic>in vivo<\/jats:italic>\n                    models, which in turn increases bioavailability and overall therapeutic efficacy of ACPD-NPs.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-63152-4","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:04:28Z","timestamp":1784631868000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biodegradable PLGA nanoparticles of acyclovir and an acyclovir prodrug for potential enhanced therapy against HSV-1 infection"],"prefix":"10.1038","volume":"16","author":[{"given":"Sushruta S.","family":"Hakkimane","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divakarareddy Vemanna","family":"Paladugulu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh L.","family":"Gaonkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitha","family":"Karunakaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piya Paul","family":"Mudgal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogeesha N.","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharath Raja","family":"Guru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"63152_CR1","unstructured":"World Health Organization. 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