Prof. Xiaozhen Li from Northwestern Polytechnical University reviewed the rencent advancement in conjugated small molecular nanoparticles for near-infrared biomedical applications

In October 2024, Prof. Xiaozhen Li from Northwestern Polytechnical University reported the recent advancement in conjugated small molecular nanoparticles (CSMNs) for near-infrared phototheranostics (NIR PTs). The article focused on the recent progress in CSMNs for NIR biological imaging, therapy, and synergistic phototheranostics, elucidating their working mechanisms from two perspectives, including photophysical and photochemical principles and light-tissue interactions. The molecular structures, structural types, optical properties, phototheranostic (PT) modes, and specific applications of PT agents based on conjugated small molecules (CSMs) were comprehensively summarized, with an emphasis on strategies for improving performances and extending absorption and emission wavelengths to the NIR range. A brief conclusion, current challenges, and possible prospects of CSMNs were finally presented. This review was published in the journal of Research titled with “Finely-Tailored Conjugated Small Molecular Nanoparticles for Near-Infrared Biomedical Applications” (Research, 2024, DOI:10.34133/research.0534).

(1) Background

Near-infrared (NIR) phototheranostics (PTs) have attracted considerable attention from researchers due to their timely monitoring of phototheranostic (PT) agents and precision therapy of disease in the NIR region. Notably, NIR PTs have clarified their superiority over PTs in the ultraviolet (UV) and visible regions regarding tissue penetration depth, signal-to-noise ratio, and biosafety. Three photo-diagnostic technologies are generally engaged, including fluorescence imaging (FLI), photoacoustic imaging (PAI), and Raman imaging (RI). Near-infrared fluorescence imaging (NIR FLI) can obtain a whole-body image, pinpointing the tumor location. PAI utilizes NIR light to stimulate ultrasonic vibration, affording deep penetration and high temporal-spatial resolution. RI is featured with a cell-silent region (1,800-2,800 cm-1), enabling zero-background imaging. Phototherapy exploits photoenergy to produce hyperthermia and toxic reactive oxygen species (ROS) for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively. PDT and PTT have become quite popular owing to their attractive merits, such as non-invasiveness, minimal side effects, and high specificity. Freely combining three photo-diagnostic technologies (FLI, PAI, and RI) and two photo-therapeutic modes (PTT and PDT) endows NIR PTs with more possibilities. However, further advancement of NIR PTs critically lies in performance optimization and absorptions/emissions wavelength extension of PT agents.

Until now, two main categories of NIR PT agents, including inorganic and organic materials, have been reported. Inorganic nanomaterials show excellent performance in NIR absorbance. However, they are always confronted with long-term toxicity concerns induced by the potential leakage of toxic heavy metal ions and minimal biodegradability, which limits their further clinical translations. In contrast, organic nanomaterials, including cyanine dyes, D-A typed conjugated small molecular nanoparticles (CSMNs), and semiconducting polymeric nanoparticles (SPNs), are more preferred in biological applications because of their good biocompatibility, favorable optical properties, low dark toxicity, and tunable optical properties. Among them, CSMNs possess higher photostability and tumor accumulation than cyanine dyes more precise molecular structures, and higher reliability than SPNs, therefore, CSMNs have good potential for in vivo imaging, tumor therapy, and multimodal diagnosis and treatment (Figure 1).

(2) Working principles of CSMNs

The working mechanisms of CSMNs are illustrated from two perspectives, including photophysical and photochemical principles and light-tissue interactions. The first is the photophysical and photochemical mechanisms of CSMNs for FLI, PAI/PTT, RI, and PDT, and the second is light-tissue interactions towards biological application (Figure 2).

(3) Strategies for regulating the absorptions of CSMs to the second near-infrared window (NIR-II)

The visible and NIR-I light hardly irradiates deep tissues because of limited penetration depth. Thus, developing NIR-II light-responsive CSMNs to improve tissue penetration depth has been an important development trend in recent years. Several strategies have been reported, including but not limited to increasing the number of thiophene bridges, building strong D-A-D conjugation, formation of J-aggregates, and molecular surgery.

(4) Applications

The article systematically summarized the application of CSMNs in the field of NIR PTs in recent years (Figure 3).

(5) Summary and outlook

Despite rapid development, some challenges remain to be addressed in CSMNs-mediated NIR PTs. The article summarized the current status of CSMNs in terms of tissue penetration depth, performance, structural design, biosafety problems, and clinical translation and proposed possible solutions and future perspectives.