Bandgap Modulation and Lipid Intercalation Generates Ultrabright D–A–D‐Based Zwitterionic Small‐Molecule Nanoagent for Precise NIR‐II Excitation Phototheranostic Applications

Abstract

Conjugated small-molecule (CSM) phototheranostic agents that operate in the second near-infrared (NIR-II) region have garnered significant attention in the field of biomedicine. However, a lack of fluorescence-emitting ability hinders their use in precise fluorescence imaging (FI)-guided photothermal therapy (PTT). Herein, a two-pronged fluorescence intensification strategy-molecular engineering for rational bandgap modulation and lipid-intercalation to combat fluorescence quenching-is used to develop NIR-II-excited ultrabright donor-acceptor-donor-based (D-A-D)-based zwitterionic CSM nanoagent for tumor phototheranostics. The molecular engineering strategy produces the NIR-II-excited D-A-D-based zwitterionic fluorophore (BTFQ) that exhibits a high NIR-II fluorescence quantum yield (QY = 0.65%) in dichloromethane. More importantly, BTFQ complexed with liposome (DMPC) to form the zwitterion-liposome nanoagent (BTFQ/DMPC) shows a negligible loss of QY (0.63%) in aqueous media. Moreover, because BTFQ/DMPC possesses excellent photothermal conversion efficiency (PCE = 30.8%) performance, it can be used to realize efficient in vivo 1064 nm single-photon high-resolution NIR-II FI guided NIR-II PTT. This study introduces a new avenue for the development of NIR-II-excited NIR-II FI/PTT agents for precise and effective tumor treatment.

Photothermal Nanomaterials: A Powerful Light-to-Heat Converter

“…Since silica-cored Au nanoshells served as the first photothermal nanomaterials for clinical use, more and more inorganic agents with strong absorption in the NIR region, high chemical stability, adjustable water solubility, and minimal cytotoxicity have entered clinical trials. , Clinical trials have also been underway for small organic molecules due to their good biodegradability, good repeatability, and simple preparation. , Nevertheless, the major challenges for the clinical implementation of photothermal nanomaterials are the complex metabolism and excretion behaviors . The representative works on PTT with diverse photothermal nanomaterials in recent years − are summarized in Table .…”

Resonance‐Enhanced Emission Effects toward Dual‐State Emissive Bright Red and Near‐Infrared Emitters

“…Fan and coworkers extended the absorption range into NIR window by increasing the number of thiophene bridges and changing the ability of the electron-withdrawing in a conjugated molecular structure. [16] Lee et al synthesized NIR-II-absorbing D-A-D based conjugated molecular structure by changing a sulfur atom to a selenium atom within an acceptor unit. [17] Up to now, molecule design was achieved by using valence bond (VB) theory which was developed in the beginning of last century and has been widely used to describe molecular structure, predict properties, and guide synthesis, etc.…”

“…For example, by introducing strong electron‐donating and withdrawing groups to promote the molecule charge transfer or extending the $${{\rm \pi }}$$ bridge to prolong electron delocalization, various fluorescent molecules have been developed. Fan and coworkers extended the absorption range into NIR window by increasing the number of thiophene bridges and changing the ability of the electron‐withdrawing in a conjugated molecular structure [16] . Lee et al.…”

Revisiting molecularly conformation-planarized organic dyes for NIR-II fluorescence imaging

“…44 Important components of most promising contrast agent candidates are donor-acceptor-donor (D-A-D) type NIR-II dyes, which feature enhanced intermolecular charge transfer, tunable photophysical properties, and large Stokes shifts. [45][46][47][48] There is a legion of D-A-D type dyes focused on enhancing fluorescence efficiency and brightness. [49][50][51][52] Among them, benzobisthiadiazole (BBT) has high electron-withdrawing ability and donors with bulky steric hindrance can force molecular structure distortion, endowing BBT-based D-A-D dyes with a high NIR-II PLQY.…”