Bio-inspired indocyanine green supramolecular assemblies for high-contrast NIR-II imaging and cooperative dual-targeting of bladder cancer.

Abstract

Developing supramolecular strategies that simultaneously regulate photophysical behavior and enable efficient biological targeting of indocyanine green (ICG) remains a major challenge for clinically compatible near-infrared region II (NIR-II) probes, as aggregation-caused quenching and ineffective tumor targeting severely limit their diagnostic potential. Here, inspired by natural light-harvesting complexes that utilize cooperative supramolecular interactions and spatial confinement to regulate chromophore behavior, we report a multi-interaction supramolecular engineering strategy to construct an ICG complex (CMPI) that simultaneously enhances photophysical performance and enables microenvironment-responsive cooperative dual targeting. A β-cyclodextrin-M2pep-aconitic acid carrier establishes a synergistic network of host-guest inclusion, electrostatic attraction, hydrogen bonding, and steric effects, which suppresses aggregation and stabilizes ICG within a spatially confined environment, thereby markedly enhancing NIR-II brightness (∼4-fold) and quantum yield (∼1.9%). In acidic tumor microenvironments, CMPI undergoes rapid charge reversal and in situ assembly, thereby amplifying the targeting of M2-like tumor-associated macrophages. Finally, CMPI prolongs circulation (half-life t_1/2 ∼14.1 min), preserves the clearance ability of ICG, and achieves a tumor-to-normal ratio of ∼11.1, enabling high-contrast NIR-II imaging and fluorescence-guided surgery across multiple bladder tumor models, including sensitive detection of sub-millimeter lesions. This strategy provides a clinically compatible supramolecular approach for simultaneously enhancing the photophysical properties and targeting of FDA-approved dyes.