A Compositionally Tunable Micelle Platform for Integrated Photoacoustic Imaging, Direct Visual Guidance, and...

Incomplete tumor resection remains a primary driver of cancer recurrence, and would benefit from technologies that enable both accurate tumor delineation and localized ablation of residual disease. Here, we report a compositionally tunable nanotheranostic platform based on sub-50 nm (~40-50 nm) poly(ethylene glycol)-block-poly(caprolactone) (PEG-PCL) nanoscale micelles co-loaded with phthalocyanine (Pc) and naphthalocyanine (Nc) dyes, designed for integrated photoacoustic (PA) imaging, direct visual guidance, and photothermal therapy (PTT). By incorporating a tetra-tert-butyl-substituted zinc phthalocyanine (ZnPc(TB)) and an octabutoxy-substituted copper naphthalocyanine (CuNc(Octa)) into micelles via both co-encapsulation and post-formulation mixing, we achieved an optimized 80:20 ZnPc(TB):CuNc(Octa) ratio that balances blue tumor coloration with high-contrast PA signals and efficient photothermal conversion. In vivo evaluation in orthotopic triple-negative breast cancer and spontaneous colorectal tumor models demonstrated that these micelles sufficiently accumulate in tumors to enable PA mapping, followed by real-time visual identification of tumor margins under white light, and efficient photothermal ablation. Notably, no difference was observed between the co-encapsulated and mixed formulations. Comprehensive hematologic analysis confirmed the platform's safety, with observed shifts attributable to procedural stress and tumor-associated physiology rather than to treatment-specific effects. These findings establish multi-chromophore Pc/Nc micelles as a versatile platform in which optical signatures can be rationally tuned to bridge the gap between deep-tissue detection, intraoperative guidance, and tumor eradication, offering a nanoscale, translatable strategy for applications such as intraoperative surgical margin assessment during breast-conserving surgery and endoscopic identification and ablation of colorectal adenomas.