Chiral Heteroatom Cluster Unlocks High-Order Multiphoton Fluorescence in Single-Benzene Luminogens

Multiphoton fluorophores are typically based on extended π-conjugated architectures, resulting in structural complexity and limited tunability. Here, we report a chirality-guided strategy for constructing high-order multiphoton fluorophores from a minimalist single-aryl scaffold. Through solvent-assisted assembly, chirality and hydrogen-bonding interactions organize heteroatoms into ordered chiral heteroatom clusters (CHCs), enabling through-space conjugation and clusteroluminescence without direct aryl–aryl π–π stacking. Structural and chiroptical studies reveal that chirality is encoded into the emissive cluster states and governs clusteroluminescence. Donor–acceptor engineering further establishes CHC-mediated through-space charge transfer in which heteroatom clusters act as electronic bridges connecting spatially separated donor and acceptor units. The synergistic interplay between chirality-guided CHC organization and charge transfer enhances electronic delocalization and polarizability, leading to efficient two-, three-, and four-photon-excited fluorescence in an isolated aromatic framework. The enhanced nonlinear optical response enables deep imaging of three-dimensional tumor spheroids with penetration depths up to 160 μm. This work establishes chirality-guided heteroatom clustering as a general strategy for compact multiphoton fluorophores and nonlinear optical materials.