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

Sep 29, 2026

NIR-II phototheranostics enable precise management of deep-seated, refractory tumors, yet optimizing multiple molecular functions remains challenging. The study introduces an S···O confirmation lock (SoCL)–based design strategy combined with synergistic alkoxy chain engineering to regulate NIR-II S-D-A-D-S planarity and improve long-wavelength emission, high fluorescence quantum yield, and conversion efficiency. IR-BTOG molecules broaden coverage across NIR-IIa and NIR-IIb, with markedly improved photothermal performance. By conjugating Glypican-3 targeting, BTOGP-GPC3 nanoparticles achieve precise HCC recognition and enhanced diagnostic capability in deep tumors.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

NIR-II phototheranostics and design challenges

D-A-D phototheranostic molecular strategies

Conformational locks and structural rigidity

Aggregation-induced emission approaches

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) S ···O Conformation Locks Synergistic Alkoxy Chain Engineering of NIR-II Phototheranostic Molecules for Precision Hepatocellular Carcinoma Theranostics Gui-long Wu ‡, Fan Wu ‡, Senyou Tan, Hao Xiao, Qiang Kang, Sanlin Deng, Fen liu, Jinkang Zheng, Chaoqiang Li, Guodong Chen,* and Qinglai Yang* 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 (􀀂ex: 1000–1300 nm) and NIR-IIb (􀀂em: 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. 1. Introduction The near-infrared II (NIR-II) spectral region (1000–1700 nm) provides advantages for precision medicine applications owing to its superior tissue penetration depth, minimized autoﬂuorescence interference, and high spatial resolution. [1–5] These remarkable optical characteristics render NIR-II-based phototheranostic molecules well-suited for addressing challenging clinical scenarios, such as deep-seated and refractory tumors. [2,6,7] Currently, within the realm of precision tumor diagnosis and treatment, the development of comprehensive phototheranostic probes that integrate near-infrared II (NIR-II) ﬂuorescence imaging with photothermal therapy (PTT)/photodynamic therapy (PDT) represents a hot point of research. It exhibits exceptional tissue penetration depth, superior photothermal conversion eﬃciency, and a high ﬂuorescence quantum yield for the incorporated NIR-II ﬂuorophore. Addressing the fundamental scientiﬁc challenge in this ﬁeld requires devising strategies toeﬀectively mitigate intramolecular energy dissipation while achieving an optimal balance among critical molecular properties, G.-long Wu, F. Wu, S. Tan, H. Xiao, Q. Kang, S. Deng, F. liu, J. Zheng, C. Li, G. Chen, Q. Yang Department of Hepatopancreatobiliary Surgery The First Aﬃliated Hospital Hengyang Medical School University of South China Hengyang, Hunan 421001, China E-mail: [chenguodong@usc.edu.cn](chenguodong@usc.edu.cn); [qingyu513@usc.edu.cn](qingyu513@usc.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202506664](https://doi.org/10.1002/advs.202506664)[ ](https://doi.org/10.1002/advs.202506664)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/adv

FAQs

What design strategy does the study propose for NIR-II phototheranostic molecules?

It proposes S···O conformation locks (SoCLs) together with synergistic alkoxy chain engineering to regulate molecular planarity and optimize multiple functional properties.

How do the IR-BTOG molecules perform across NIR-II regions?

They extend optical coverage into both NIR-IIa (1000–1300 nm) and NIR-IIb (1500–1700 nm) regions while achieving high fluorescence quantum yields and significantly improved photothermal performance.

How are the nanoparticles targeted to hepatocellular carcinoma (HCC)?

BTOGP-GPC3 nanoparticles are developed by conjugating the HCC-specific targeting Glypican-3 (GPC3) peptide, enabling precise recognition and diagnosis of HCC.

Sep 29, 2026

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