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Mater."],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>This study investigates the efficacy of phytochemical nanoformulations\u2014specifically curcumin and thymoquinone (TQ) delivered via gold nanoparticles (AuNPs)\u2014against melanoma A375 cells in both 2D and 3D bioprinted gelatin-alginate scaffolds. Phytochemicals such as curcumin, TQ, epigallocatechin gallate, and betulin exhibit multi-target anticancer effects, but their clinical translation is limited by poor solubility, rapid metabolism, and low tumor penetration. We compared free phytochemicals, AuNP co-administration, and AuNP-phytochemical conjugates, assessing their effects on viability, ROS generation, and mitochondrial membrane potential over time. In 2D cultures, all agents exhibited dose-dependent cytotoxicity, with curcumin and TQ proving to be the most potent. However, in 3D scaffolds mimicking tumor microenvironments, only AuNP-phytochemical conjugates sustained mitochondrial and redox stress, overcoming adaptation barriers and providing durable suppression of melanoma viability. Free and co-administered agents displayed metabolic rebound and limited efficacy due to diffusion constraints and extracellular matrix-driven resistance. Unlike prior studies that investigate either free phytochemicals or nanoparticle delivery in isolation, this work integrates 2D and 3D bioprinted A375 melanoma constructs to directly compare free, co\u2010administered, and gold\u2010nanoparticle\u2013conjugated phytochemicals. We show that only conjugated AuNP\u2013phytochemical formulations sustain mitochondrial and redox stress long enough to overcome 3D adaptation barriers, establishing a delivery\u2010strategy\u2013dependent framework for preclinical evaluation of phytochemical nanomedicines.<\/jats:p>","DOI":"10.1088\/1748-605x\/ae5ee7","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T22:56:08Z","timestamp":1776120968000},"page":"035004","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["3D bioprinted melanoma constructs reveal delivery-dependent efficacy of phytochemical-gold nanoparticle formulations"],"prefix":"10.1088","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0250-3034","authenticated-orcid":true,"given":"Muge Kasim","family":"Kirac","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bar\u0131\u015f","family":"Bilge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9420-567X","authenticated-orcid":true,"given":"Cansu Canbek","family":"Ozdil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuna","family":"Tugcu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3668-3467","authenticated-orcid":true,"given":"Kutlu O","family":"Ulgen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"266","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"bmmae5ee7bib1","doi-asserted-by":"publisher","first-page":"707","DOI":"10.3390\/cancers17040707","type":"journal-article","article-title":"Clinical approaches for the management of skin cancer: a review of current progress in diagnosis, treatment, and prognosis for patients with melanoma","volume":"17","author":"Connor","year":"2025","journal-title":"Cancers"},{"key":"bmmae5ee7bib2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","type":"journal-article","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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