Figure 1. (a) Schematic illustration of the multifunctional theranostic platform co-loaded with IR820, ZnCdSe/ZnS QDs and CQ for MPTT. (b) TEM images of PIFC NPs. (c) UV–Vis spectra of CQ, PLGA NPs, IR820 and PIFC NPs. (d) Heating and cooling curves of PIFC NPs and IR820 irradiated by 808 nm laser (1.0 W/cm²) over four ON/OFF cycles. Reproduced from Ref. [94] with permission. Copyright 2022 Elsevier.

3.1.2. D-A structured small molecules

Donor–acceptor (D–A) structure is an effective means to regulate the molecular energy band, which can reduce the oxidation potential and have higher stability. So far, many D–A molecules have been reported, such as benzothiadiazole, quinoxaline and their derivatives.[95-98] The D–A structure can not only reduce the band gap of the molecule and expand the absorption range of the molecule, but also explore the influence of different functional groups on the properties of the material. D–A structured small molecule fluorophores with properties such as excellent biocompatibility, minimal cellular toxicity, straightforward chemical modifiability, and favorable excretion pharmacokinetics in biological systems are highly sought after for potential clinical applications in NIR-II (1000-1700 nm) diagnostic imaging and therapy.[99-101] Nonetheless, standalone organic molecules often lack traits like tumor-targeting ability and water solubility. Addressing these challenges involves employing strategies such as PEGylation or generating nanometric forms. These approaches not only prevent rapid renal or hepatic clearance of organic dyes but also extend their circulation within the bloodstream. Furthermore, these NPs tend to accumulate effectively in tumor tissues due to the enhanced permeability and retention (EPR) effect.[102-104] Hu et al. employed D–A molecular engineering to fabricate efficient small organic molecules termed TD1 via anchoring the electron deficient thiadiazolobenzotriazole (TBZ) core with 2,2′-bithiophene, triphenylamine (TPhT) rotors, and encapsulated within lipid carriers, creating mitochondria-targeted NPs known as M-TD1 NPs for MPTT. Mechanistically, the improved mild thermal treatment at the mitochondrial level triggers apoptosis-dependent cell death and modulates cancer cell autophagy.[105] These combined effects lead to an intensified eradication of cancer cells and a concurrent suppression of cancer cell migration. Liu et al. introduced a novel concept of NIR responsive and dual-sensitized NPs centered around a chromophore combination of two perylene monoimides and a diamino anthraquinone (2PMI-AQ), forming an inner hydrophobic core. To harness the sensitized functionality, the hydrophilic thermosensitive polymers were incorporated into the modified 2PMI-AQ, resulting in the formation of stable NPs referred to as NP1. The external thermosensitive NP1 facilitate the loading and controlled photothermal release of HSP90 inhibitors.[106] Upon NIR laser irradiation, the synergistic effects of photothermal and photodynamic actions are harnessed alongside the controlled release of HSP90 inhibitors, thereby enhancing both MPTT and photodynamic therapy (PDT) efficacy. Sun et al. reported an engineered probes comprise two distinct H₂O₂-activatable PTAs, namely aza-BOD-B1 with a single activatable site and aza-BOD-B2 with multiple activatable sites. Upon interaction with H₂O₂, aza-BOD-B1 demonstrates a modest absorption redshift of 60 nm, spanning from 750 nm to 810 nm. However, this shift results in significant spectral overlap, leading to only a mild photothermal effect on normal tissues when subjected to 808 nm light irradiation. In contrast, aza-BOD-B2 exhibits a substantial absorption spectral separation spanning 150 nm, ranging from 660 nm to 810 nm.[107] This impressive spectral separation facilitates genuine selective activation, thereby minimizing the risk of side effects during cancer-focused MPTT. This study represents a practical solution to the persisting challenge of undesired side effects in MPTT, marking a significant stride forward in the realm of precision medicine. Zhu et al. introduced a novel approach to formulating a MPTT nanotherapeutic platform by utilizing the self-assembly of a pH-responsive phenothiazinium dye with an impressive PCE of up to 84.5%. Remarkably, they require an exceptionally low light dose of only 36 J/cm² to achieve efficient MPTT of bacteria at pH 5.5, achieved through 650 nm laser irradiation. Furthermore, this intelligent nanoplatform exhibited a unique property of transitioning from a negative to a positive charge in acidic biofilm environments. This characteristic allowed for effective penetration and highly efficient eradication of drug-resistant E. coli biofilms when subjected to photoirradiation. The effectiveness of this nanoplatform was further validated through in vivo animal tests, demonstrating its capacity for bacterial elimination and mitigation of inflammation. Importantly, these PTAs also showcased excellent biocompatibility and biosafety during the treatment of ocular bacterial infections (Figure 2).[108] In conclusion, this efficient single-component MPTT system, characterized by its straightforward construction processes, holds immense potential for widespread applications and eventual clinical translation.