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Herein, we present a general building\u2010block design for ultralow\u2010molecular\u2010weight \u201czero\u2010on\u201d near\u2010infrared\u2010II photoacoustic dyes for in vivo high\u2010fidelity imaging. Constructed around a dimethyl\u2010dihydroacridine scaffold and synthesized in three steps, these dyes incorporate biomarker\u2010responsive blocks for targeted activation and absorption\u2010expanded blocks for near\u2010infrared\u2010II absorption tuning, while maintaining a molecular weight &lt;500\u00a0Da. This general building\u2010block design enables tailored applications. Ultralow molecular weight improves solubility, tissue penetration and clearance. Notably, biomarker activation drives nonconjugated\u2010to\u2010conjugated structural transition, inducing &gt;700\u00a0nm absorption redshift and boosting near\u2010infrared\u2010II photoacoustic signals at 1064\u00a0nm from levels statistically indistinguishable from water (\n                    <jats:italic>p<\/jats:italic>\n                    &gt; 0.05, defining \u201czero\u201d probe background) to an 89.8\u2010fold enhancement in \u201con\u201d state. \u201cZero\u201d background minimizes false positives from misinterpreting probe background accumulation signals in diseased tissues as biomarker activation, even in high\u2010uptake organs like the liver. In a blinded study, our \u201czero\u2010on\u201d probes identified early\u2011stage hepatotoxicity in mice with 100% accuracy, outperforming 85% accuracy of traditional non\u2010zero background \u201coff\u2013on\u201d probes. This work enables a general design to achieve ultralow\u2010molecular\u2010weight near\u2010infrared\u2010II photoacoustic dyes for high\u2010fidelity signal output in vivo.\n                  <\/jats:p>","DOI":"10.1002\/anie.7119524","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:14:36Z","timestamp":1786014876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A General Design of Compact \u201cZero\u2010On\u201d NIR\u2010II Photoacoustic Dyes for High\u2010Fidelity Imaging"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8038-3302","authenticated-orcid":false,"given":"Chunxu","family":"He","sequence":"first","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) &amp; Institute of Advanced Materials (IAM) Nanjing University of Posts &amp; Telecommunications  Nanjing 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