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However, HMC dyes are typically amphiphilic molecules, leading to non\u2010specific binding to blood proteins, primarily albumin, following systemic administration. While albumin binding can extend blood circulation time and enhance tumor accumulation, it can also lead to significant healthy tissue uptake, resulting in low tumor\u2010to\u2010background signal ratios (TBR) and potential toxicity. Here, we report a molecular shielding strategy to prevent non\u2010specific protein binding of tumor\u2010targeting HMC dyes. We develop a rationally designed library of molecularly shielded NIR fluorescent probes based on a clinically approved HMC dye, indocyanine green (ICG). To shield non\u2010specific protein interactions of ICG, its sidechain is modified with varying numbers of charged amino acid residues, which transformed ICG into a low protein binding, renal\u2010clearable pan\u2010cancer targeting probe. These shielded ICG molecules showed strong tumor accumulation and optimal tissue clearance in a few days, enabling high\u2010contrast tumor imaging with TBR values reaching 8 and clear tumor margins in orthotopic rodent tumor models. These new tumor\u2010targeting NIR probes represent a clinically translatable platform for cancer detection and therapy with a modular molecular structure composed of non\u2010toxic, FDA\u2010approved components.<\/jats:p>","DOI":"10.1002\/adfm.76263","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:59:14Z","timestamp":1782125954000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Molecular Shielding Strategy to Develop Low Protein Binding, Renal Clearable Pan\u2010Cancer Near\u2010Infrared Probes"],"prefix":"10.1002","volume":"36","author":[{"given":"Li","family":"Xiang","sequence":"first","affiliation":[{"name":"CEDAR Knight Cancer Institute School of Medicine Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailin","family":"Mooney","sequence":"additional","affiliation":[{"name":"CEDAR Knight Cancer Institute School of Medicine Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingchong","family":"Dai","sequence":"additional","affiliation":[{"name":"CEDAR Knight Cancer Institute School of Medicine Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan R.","family":"Stewart","sequence":"additional","affiliation":[{"name":"CEDAR Knight Cancer Institute School of Medicine Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Holland","sequence":"additional","affiliation":[{"name":"Neuro\u2010Oncology Blood\u2010Brain Barrier Program Oregon Health and Science University  Portland Oregon USA"},{"name":"Department of Radiology School of Medicine Oregon Health and Science University  Portland Oregon 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