Engineering Synergistic Intra‐/Intermolecular Conformational Locking via Side‐Chain Branching: A β‐Sheet‐Inspired Strategy for Planar NIR‐II Phototheranostic Aggregates

ABSTRACT Engineering stable noncovalent conformational locks (NoCL) network at the aggregate level is essential for developing phototheranostic aggregates (PTAs) with enhanced rigidity and light‐harvesting ability, but remains a challenge due to complex intermolecular interactions. Inspired by β‐sheet proteins, where branched side chains act as steric directors to program backbones into interlocked architectures, a side‐chain isomerization strategy is proposed to manipulate analogous NoCL networks for constructing planar‐structured NIR‐II multimodal PTAs. Two isomeric pairs with linear ( l ‐series) and branched ( b ‐series) alkyl side‐chains are synthesized. Crystallographic analysis reveals that the b ‐series, driven by directional S···O/F interactions, adopts a fully planar conformation stabilized by a synergistic dual NoCL network, whereas l ‐series exhibits twisted conformations. Theoretical calculation and femtosecond transient absorption spectra confirm the dual NoCL network effectively narrows the energy gap and optimizes excited‐state energy dissipation pathway, resulting in comprehensive enhancement in phototheranostic performance including superior ROS generation, higher NIR‐II brightness and excellent photothermal properties compared to l ‐series NPs. Notably, the exceptional performance of b ‐3CPFIC NPs enables it to serve as an ideal candidate in multimodal NIR‐II phototheranostics of tumors. This work establishes a novel design paradigm for multifunctional PTAs and elucidates aggregate‐level structure–property relationships.