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Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long\u2010acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine [AZT]) over 28 days. The formulation is a self\u2010assembling ultrashort\n                    <jats:sc>d<\/jats:sc>\n                    or\n                    <jats:sc>l<\/jats:sc>\n                    \u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    peptide hydrogelator, namely phosphorylated (naphthalene\u20102\u2010ly)\u2010acetyl\u2010diphenylalanine\u2010lysine\u2010tyrosine\u2010OH (NapFFKY[p]\u2010OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrates phosphatase enzyme instructed self\u2010assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggest hydrogels form narrow radius (\u22482\u00a0nm), large length fibers closely fitting the flexible cylinder elliptical model.\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Peptides are particularly promising for long\u2010acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progress under physiological conditions (37\u00a0\u00b0C, pH 7.4, H\n                    <jats:sub>2<\/jats:sub>\n                    O). Subcutaneous administration of Napffk(AZT)Y[p]G\u2010OH in Sprague Dawley rats demonstrate zidovudine blood plasma concentrations within the half maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) range (30\u2013130\u00a0ng mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) for 35 days. This work is a proof\u2010of\u2010concept for the development of a long\u2010acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202203198","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T04:55:35Z","timestamp":1678164935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Enzyme\u2010Triggered\n                    <scp>l<\/scp>\n                    \u2010\n                    <i>\u03b1<\/i>\n                    \/\n                    <scp>d<\/scp>\n                    \u2010Peptide Hydrogels as a Long\u2010Acting Injectable Platform for Systemic Delivery of HIV\/AIDS Drugs"],"prefix":"10.1002","volume":"12","author":[{"given":"Sophie M.","family":"Coulter","sequence":"first","affiliation":[{"name":"School of Pharmacy Queen's University Belfast Medical Biology Centre  97 Lisburn Road Belfast, Co. 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