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.