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By tuning the nucleophilicity of the ortho-carboxy moiety, we achieved an electronic effect termed \u201cfirm-push-to-open and light-push-to-lock,\u201d which enables complete spirocyclization of the probe before sensing and allows for efficient zwitterion formation when the light-pushing aniline carbamate trigger is transformed into a firm-pushing aniline. This platform produces dual-modality NIR-II imaging probes with ~50-fold fluorogenic and activatable photoacoustic signals in live mice, surpassing reported probes with generally below 10-fold activatable signals. Demonstrating generality, we successfully designed probes for hydrogen peroxide (H\n            <jats:sub>2<\/jats:sub>\n            O\n            <jats:sub>2<\/jats:sub>\n            ) and hydrogen sulfide (H\n            <jats:sub>2<\/jats:sub>\n            S). We envision a widespread adoption of the chemical platform for designing activatable NIR-II probes across diverse applications.\n          <\/jats:p>","DOI":"10.1126\/sciadv.ado2037","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T17:58:18Z","timestamp":1718387898000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":21,"title":["A firm-push-to-open and light-push-to-lock strategy for a general chemical platform to develop activatable dual-modality NIR-II probes"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0898-0920","authenticated-orcid":true,"given":"Lili","family":"Shen","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Street, Hangzhou 310058, 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