{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:40Z","timestamp":1792789300130,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EPSRC","award":["EP\/S031561\/1"],"award-info":[{"award-number":["EP\/S031561\/1"]}],"id":[{"id":"https:\/\/ror.org\/0439y7842","id-type":"ROR","asserted-by":"crossref"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["813440"],"award-info":[{"award-number":["813440"]}]},{"name":"Rajshri Shahu Maharaj Foreign Studies Scholarship, the Department of Social Justice and Social Empowerment, Government of Maharashtra, Pune, India","id":[{"id":"https:\/\/ror.org\/057ykey20","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/057ykey20","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>Sustained postoperative anti-inflammatory therapy following intraocular surgery remains an unmet clinical need, as conventional topical corticosteroid eye drops suffer from poor bioavailability, patient non-compliance, and an inability to maintain therapeutic drug levels over the multi-week inflammatory resolution period. Here we report the development and characterization of alkaline phosphatase (ALP)-responsive enzyme-instructed self-assembling (EISA) peptide hydrogels based on the ultrashort amphiphilic sequence NapFFKY(p)-OH, covalently conjugated with dexamethasone (DEX) via an ester-cleavable succinyl linker, in both L- and D-enantiomeric forms, as injectable platforms for subconjunctival drug delivery. Both conjugates, L-NapFFK(DEX)Y(p)-OH and D-NapFFK(DEX)Y(p)-OH, were synthesized with chemical purity (87.3% and 89.8%, respectively) and theoretical DEX loading of 29.58% w\/w. ALP-triggered gelation was confirmed for both enantiomeric gels at 2% w\/v, with rheological characterization of the platform establishing a storage modulus plateau of approximately 294 Pa, a G\u2032\/G\u2033 ratio of ~10:1, and gel failure at approximately 578% shear strain. Transmission electron microscopy revealed stereochemistry-dependent differences in nanofiber network architecture, with the D-enantiomer forming a comparatively looser, more porous fibrillar matrix than its L-counterpart. In vitro DEX release over 28 days demonstrated that covalent conjugation eliminates the burst release associated with physical drug entrapment (41.1% for the L physical mixture versus 14.2% and 8.3% for L- and D-conjugated systems, respectively, at 2% w\/v), while D-amino acid stereochemistry provides an additional level of sustained release restraint. Proteinase K stability studies confirmed the exceptional proteolytic resistance of the D-enantiomer, retaining 92.6 \u00b1 2.2% of intact peptide at 6 h compared with 25.3 \u00b1 0.8% for the L-enantiomer. Ex vivo scleral permeation studies demonstrated a trend towards greater cumulative DEX permeation (10.6 vs. 6.7 \u00b5g) and tissue retention (5.6 vs. 3.2 \u00b5g) for the D vs. L-formulation over 24 h. Both formulations exhibited injection forces within acceptable limits for a 30-gauge needle for ophthalmic administration, with the D-enantiomer requiring lower force than its L-counterpart. Cell viability of Dex-conjugated peptide sequence demonstrated non toxic in ARPE-19 human retinal pigment epithelial cells across all conditions tested, confirming biocompatibility. These findings establish the backbone stereochemistry independently controls network mechanics, proteolytic stability, and drug release rate in ALP-responsive EISA hydrogels. Cumulative release over 28 days remains below that required to cover a 4\u20136-week postoperative course, and this work is therefore presented as a mechanistic proof-of-concept defining design principles for the platform rather than a clinically optimized formulation. Drug loading, peptide sequence, and linker chemistry are identified as the levers through which release rate may be matched to intended clinical interval.<\/jats:p>","DOI":"10.3390\/gels12090850","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:19:03Z","timestamp":1790086743000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enzyme-Instructed Self-Assembling Peptide Hydrogels for Sustained Subconjunctival Delivery of Dexamethasone: A Stereochemical Comparison of L- and D-Enantiomeric Peptides for Postoperative Ocular Anti-Inflammatory Therapy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-2454","authenticated-orcid":false,"given":"Shubhamkumar M.","family":"Baviskar","sequence":"first","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5021-6825","authenticated-orcid":false,"given":"Deepakkumar","family":"Mishra","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-9066","authenticated-orcid":false,"given":"Lalitkumar","family":"Vora","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1435-2942","authenticated-orcid":false,"given":"Garry","family":"Laverty","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8513-1215","authenticated-orcid":false,"given":"Sreekanth","family":"Pentlavalli","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"},{"name":"Centre for Pharmaceutical Engineering Science (CPES), School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7582-2082","authenticated-orcid":false,"given":"Raghu Raj Singh","family":"Thakur","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e489","DOI":"10.1016\/S2214-109X(20)30488-5","article-title":"The Lancet Global Health Commission on Global Eye Health: Vision beyond 2020","volume":"9","author":"Burton","year":"2021","journal-title":"Lancet Glob. 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