S···O Conformation Locks Synergistic Alkoxy Chain Engineering of NIR‐II Phototheranostic Molecules for Precision Hepatocellular Carcinoma Theranostics

NIR‐II phototheranostics offers a promising strategy for precisely managing deep‐seated and refractory tumors. However, the overall optimization of molecular functional properties remains a challenge, and due to the lack of a comprehensive design strategy, there have been limitations in achieving long‐wavelength phototherapy, high‐fluorescence quantum yield, and photothermal/photodynamic conversion efficiency. This study initially proposes an innovative strategy that involves S···O confirmation locks (SoCLs), synergistic alkoxy chain engineering, and the regulatory influence of the SoCLs on NIR‐II S‐D‐A‐D‐S‐type (shield‐donor‐acceptor‐donor‐shield) molecular planarity and successfully optimizes the molecular structure. The resulting IR‐BTOG molecules exhibit extended coverage across the NIR‐IIa (λex: 1000–1300 nm) and NIR‐IIb (λem: 1500–1700 nm) regions, achieving high fluorescence quantum yields and significantly improved photothermal performance. Building on this molecular design, BTOGP‐GPC3 nanoparticles (NPs) are further developed by conjugating the hepatocellular carcinoma (HCC)‐specific targeting molecule Glypican‐3 peptide (GPC3). This conjugation enables precise recognition and diagnosis of HCC. The excellent phototheranostic performance of BTOGP‐GPC3 NPs confirms that the SoCLs synergistic alkoxy chain modification strategy markedly enhances the diagnostic performance of the molecule in deep‐seated tumors, offering novel opportunities for applying precision phototheranostics in HCC. Moreover, it provides a significant structural design foundation for the future advancement of NIR‐II phototheranostic formulations.