{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:26:29Z","timestamp":1786123589321,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Planning Project of Anhui Province","award":["2022AH051055"],"award-info":[{"award-number":["2022AH051055"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Mesoporous silica nanoparticles (MSNs) are widely investigated as nanocarriers for drug delivery, gene transfer, and bioimaging. However, the mechanisms underlying their size-dependent cytotoxicity at the metabolic level remain incompletely understood. This study aimed to determine whether different-sized MSNs induce distinct patterns of subcellular injury and metabolic reprogramming in lung epithelial cells. Methods: A549 cells were exposed to 80 nm and 600 nm MSNs at 50 and 200 \u03bcg\/mL for 24 h. Ultrastructural changes were examined by transmission electron microscopy (TEM). Intracellular reactive oxygen species (ROS) and Ca2+ were measured by 2\u2032,7\u2032-dichlorodihydrofluorescein diacetate (DCFH-DA) and Fluo-4 AM fluorescence, respectively. Inflammatory gene expression (IL1B, IL6, TNFA, HIF1A) was quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Untargeted metabolomics were performed using combined gas chromatography\u2013mass spectrometry (GC-MS) and liquid chromatography\u2013mass spectrometry (LC-MS) platforms, followed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and MetaboAnalyst-based pathway enrichment. Results: TEM revealed distinct size-dependent subcellular distributions: 80 nm MSNs were predominantly associated with mitochondrial abnormalities, including cristae disruption, swelling, and mitophagy-like features, whereas 600 nm MSNs accumulated in endocytic vesicles with membrane disruption. Metabolomic profiling showed that 80 nm MSNs were associated with TCA cycle blockade\u2014characterized by the accumulation of early intermediates (citrate, oxaloacetate) and the depletion of distal intermediates (fumarate, malate)\u2014with compensatory glycolytic activation (increased glyceraldehyde-3-phosphate and pyruvate) and reduced deoxynucleotide pools (dCDP, dUMP). By contrast, 600 nm MSNs triggered broad nucleotide triphosphate accumulation (ATP, CTP, dGTP, dCTP), amino acid depletion, and robust inflammatory activation, including a ~136-fold increase in IL1B expression and HIF1A transcriptional upregulation. PCA and PLS-DA confirmed distinct size-dependent metabolic phenotypes. Conclusions: MSN size strongly influences subcellular targeting\u201480 nm particles were predominantly associated with mitochondrial injury while 600 nm particles disrupted endocytic vesicles\u2014driving qualitatively distinct patterns of metabolic reprogramming and inflammatory signaling. These findings establish a correlative mechanistic framework linking particle size to organelle-specific injury and provide candidate metabolic markers for nanotoxicological evaluation.<\/jats:p>","DOI":"10.3390\/metabo16080559","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:00:43Z","timestamp":1786118443000},"page":"559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Size-Dependent Metabolic Reprogramming in A549 Cells Induced by Mesoporous Silica Nanoparticles: Insights from Subcellular Targeting"],"prefix":"10.3390","volume":"16","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Modeling, Simulation and Control of Complex Ecological Model in Dabie Mountains of Anhui Higher Eduction Institutes, School of Physics and Astronomy, Anqing Normal University, Anqing 246133, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Laborator of Nano-Biology Technology, Institute of Super-Microstructure and Ultrafast Process in Advanced Materials, School of Physics, Central South University, Changsha 410083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.addr.2008.03.012","article-title":"Mesoporous Silica Nanoparticles as Controlled Release Drug Delivery and Gene Transfection Carriers","volume":"60","author":"Slowing","year":"2008","journal-title":"Adv. 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