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Although ions, alcohols, and urea have been extensively characterized, the effect of nucleic acids remains largely unexplored. This study systematically investigates the LCST behavior of PNIPAM in the presence of single-stranded DNA (ssDNA) with varying base compositions (A, T, G, C), chain lengths (10\u201360 residues), and concentrations (0\u201325,600 \u03bcMres) using differential scanning calorimetry. ssDNAs reduce the LCST, with base-type effects following A &amp;gt; T &amp;gt; G \u2248 C and weaker effects observed for shorter chains at equivalent residue concentrations. These trends indicate a mechanism driven by indirect water-mediated interactions. By decomposing the transition energy into solvent-excluded volume, intramolecular and intermolecular attractions, and conformational entropy, the chaotropic behavior of ssDNA is observed. The intermolecular attraction term shows a second-order dependence on ssDNA concentration, consistent with preferential partitioning into the polymer hydration shell. Moreover, this attraction term for a mixed-base sequence can be estimated from single-base coefficients using composition-weighted averaging. The approach accurately predicts the LCST of PNIPAM in the presence of let-7a ssDNA, a 22-nucleotide ssDNA analog of microRNA let-7a, demonstrating good agreement (RMSD = 1.5 \u00d7 10\u20132 \u00b0C for LCST, 6.2 \u00d7 10\u20133 kJ\/mol for \u0394Ea). This study establishes a quantitative framework for predicting the effects of nucleic acid cosolutes on PNIPAM LCST.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c04064","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:02:00Z","timestamp":1787025720000},"page":"9286-9299","source":"Crossref","is-referenced-by-count":0,"title":["Effect of Single-Stranded DNA on the Lower Critical\nSolution Temperature of Poly(\n                    <i>N<\/i>\n                    -isopropylacrylamide):\nImplications for Thermoresponsive Polymer\u2013Nucleic Acid Systems"],"prefix":"10.1021","volume":"130","author":[{"given":"Runze","family":"Huang","sequence":"first","affiliation":[{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-Cho , , ,","place":["Midori-Ku, Yokohama, Japan, 226-8501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5744-3679","authenticated-orcid":true,"given":"Kyohei","family":"Okubo","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-Cho , , ,","place":["Midori-Ku, Yokohama, Japan, 226-8501"]},{"name":"Institute of Science Tokyo , , 1-5-45 Yushima , , ,","place":["Bunkyo-Ku, Tokyo, Japan, 113-8549"]},{"name":"Institute of Science Tokyo , , 1-5-45 Yushima , , ,","place":["Bunkyo-Ku, Tokyo, Japan, 113-8549"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zizhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-Cho , , ,","place":["Midori-Ku, Yokohama, Japan, 226-8501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5051-6668","authenticated-orcid":true,"given":"Yoshitaka","family":"Kitamoto","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-Cho , , ,","place":["Midori-Ku, Yokohama, Japan, 226-8501"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"24","key":"2026091008080922600_cit1","doi-asserted-by":"publisher","first-page":"6024","DOI":"10.1021\/ja01000a006","article-title":"Slow Hydrogen-Deuterium\nExchange\nin a Non-.Alpha.-Helical Polyamide","volume":"89","author":"Scarpa","year":"1967","journal-title":"J. Am. Chem.\nSoc."},{"issue":"12","key":"2026091008080922600_cit2","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1016\/j.progpolymsci.2004.08.003","article-title":"Stimuli-Reponsive Polymers and Their Bioconjugates","volume":"29","author":"Gil","year":"2004","journal-title":"Prog. Polym. Sci."},{"issue":"2","key":"2026091008080922600_cit3","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.jcis.2010.05.034","article-title":"Poly(N-Isopropylacrylamide)\n(PNIPAM) Is Never Hydrophobic","volume":"348","author":"Pelton","year":"2010","journal-title":"J. Colloid Interface\nSci."},{"issue":"13","key":"2026091008080922600_cit4","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.1039\/D0TB02877K","article-title":"Recent Advances in Thermo-Sensitive Hydrogels for Drug Delivery","volume":"9","author":"Yu","year":"2021","journal-title":"J. Mater. Chem. 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Polym. Mater."},{"issue":"8","key":"2026091008080922600_cit8","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1080\/10601326808051910","article-title":"Solution Properties\nof Poly(N-Isopropylacrylamide)","volume":"2","author":"Heskins","year":"1968","journal-title":"J. Macromol.\nSci. Part - Chem."},{"issue":"51","key":"2026091008080922600_cit9","doi-asserted-by":"publisher","first-page":"15342","DOI":"10.1002\/anie.201506663","article-title":"Poly(N-Isopropylacrylamide) Phase\nDiagrams: Fifty Years of Research","volume":"54","author":"Halperin","year":"2015","journal-title":"Angew. Chem.,\nInt. Ed."},{"issue":"10","key":"2026091008080922600_cit10","doi-asserted-by":"publisher","first-page":"4352","DOI":"10.1021\/j100373a088","article-title":"Microcalorimetric Detection of Lower Critical Solution\nTemperatures in Aqueous Polymer Solutions","volume":"94","author":"Schild","year":"1990","journal-title":"J.\nPhys. 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