Emerging Designs of Aggregation-Induced Emission Agents for Enhanced Phototherapy Applications

Open AccessCCS ChemistryMINI REVIEW1 Feb 2022Emerging Designs of Aggregation-Induced Emission Agents for Enhanced Phototherapy Applications Rui Qu, Xu Zhen and Xiqun Jiang Rui Qu MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093 , Xu Zhen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093 and Xiqun Jiang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093 https://doi.org/10.31635/ccschem.021.202101302 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), that employs phototherapeutic agents to generate cytotoxic reactive oxygen species (ROS) or hyperthermia, is a promising approach for disease therapy. However, conventional organic phototherapeutic agents suffer poor photostability and aggregation-caused quenching (ACQ) in the aggregate state, restricting their therapeutic efficacy. Aggregation-induced emission (AIE) agents can solve these issues with strong emission in the aggregate state and reverse designation to generate heat. This review summarizes the recent advances in the development of AIE phototherapy agents for enhanced PDT and PTT performances in biomedical applications. First, design strategies of AIE agents that adjust the intersystem crossing process or intramolecular charge transfer to boost ROS generation or regulate ROS types are discussed. The AIE agents with ROS generation ability for biomedical applications including antitumor and antibacterial performances are then introduced. Next, designs and examples of AIE agents that enhance PTT performances through molecular motions are described. Finally, the current challenges and perspectives of AIE agents in the phototherapy field are discussed. Download figure Download PowerPoint Introduction Phototherapy that utilizes photoirradiation to generate cytotoxic reactive oxygen species (ROS) for photodynamic therapy (PDT) or hyperthermia for photothermal therapy (PTT) is a promising approach for disease therapy because of its non-invasiveness, negligible drug resistance, high therapeutic selectivity and efficacy, and minimized off-target side effects.1–7 Organic contrast agents have attracted much attention in the phototherapy field due to their excellent optical properties and tunable molecular structures.8–11 However, the traditional small molecular organic contrast agents used for phototherapy such as rose bengal analogs, methylene blue, and cyanine derivatives, suffer from poor photostability and aggregation-caused quenching (ACQ) in the aggregate state after they are transformed into water-soluble nanoparticles, leading to a relatively low therapeutic efficacy.12–14 Organic contrast agents with aggregation-induced emission (AIE) phenomena are contrary to the traditional contrast agents with the ACQ effect.15–19 The AIE agents are almost non-emissive in the isolated molecular state but strongly emissive in the aggregate form.20–22 This phenomenon is due to the restriction of intramolecular motion (RIM) of AIE agents in the aggregated state, which avoids the nonradiative decay that dissipates the absorbed light, and thus leads to the enhanced fluorescence emissions.23,24 Meanwhile, the non-planar structure of AIE agents also contributes to circumventing π–π interactions and activates strong emission in aggregated state.25 Because of such a special molecular structure, AIE agents have been developed into optical probes for long-term cell tracking, tumor imaging, and image-guided surgery.26–28 Recently, AIE agents were reported to show strong photosensitization and high photothermal conversion efficiency through molecular engineering.29–31 Introducing an electron-rich anion-π+ structure into AIE agents results in the highly efficient ROS generation for PDT.32,33 In addition, the disease microenvironment often suffers from hypoxia which limits the generation efficacy of singlet oxygen by AIE photosensitizers (PSs) through the energy transfer process from excited triplet AIE PSs to triplet oxygen.34,35 Another type of AIE PS that depends on the electron transfer from excited AIE PSs to oxygen to produce free radical ROS has obtained more and more attention.33,36 With the help of rotors and spacer structures, the molecular motions of AIE agents in the aggregate state can be tuned to enhance the nonradiative decay, providing guidelines for the development of AIE agents for PTT applications.37–40 In this review, we summarize the recent advances in the design strategies of AIE agents for enhanced PDT and PTT performances. The chemical structures of AIE agents used for enhanced PDT and PTT performances are summarized in Schemes 1 and 2. The design strategies of AIE agents through adjusting the intersystem crossing (ISC) process or intramolecular charge transfer (ICT) to boost ROS generation or regulate ROS types under laser irradiation are first discussed. Next, we review the AIE agents with ROS generation ability for biomedical applications including antitumor and antibacterial performances. Then, designs and examples of AIE agents to enhance PTT performances through molecular motions are described. Finally, a summary and current challenges and perspectives of AIE agents in the phototherapy field are given. Scheme 1 | Chemical structures of AIE agents for PDT. Download figure Download PowerPoint AIE Agents with ROS Generating Ability Design strategies to enhance the photosensitizing performance of AIE agents PDT that relies on PSs and laser irradiation to produce ROS is an emerging therapeutic modality for diseases.41–45 According to the Jablonski diagram (Figure 1a), after the excitation light is absorbed by the PSs, the electrons of PSs are excited from the ground state (S0) to the excited state (Sn), and the electrons at the Sn state dissipate the energy and return to the singlet excited state (S1) through the relaxation process. There are three major energy dissipation pathways from S1 to S0: radiative decay to produce fluorescence emission, nonradiative decay to generate heat for PTT, and ISC to the triplet excited state (Tn) to produce ROS for PDT.39 The ROS produced by PSs mainly includes two types: Type I PSs produce radical species including superoxide anion (O2•−) and hydroxyl radicals (OH•) through electron transfer from excited PSs to oxygen species, whereas type II PSs utilize energy transfer between triplet states of PSs and oxygen to produce singlet oxygen (1O2).46,47 The key step for enhancing ROS generating efficiency is the ISC process.48,49 Promoting the ISC process and creating rich triplet-state energy levels show potential for improving the ROS generating efficiency. Figure 1 | (a) Schematic diagram of the fundamental mechanism for photosensitizing process. (b) Molecular structure designed according to “small ΔEST enhances ISC efficiency”. (c) Schematic illustration of ROS generation through different routes: Type I electron transfer to form radical ROS and H2O2, type II energy transfer to form singlet oxygen. (d) Chemical structure and designing strategies for anion-π+ structure. (e) Scheme of type I PSs designation utilizing electron transfer during the photochemical process. Figures a and b are reprinted with permission from ref 31. Copyright 2019 American Chemical Society. Figures c and d are reprinted with permission from ref 33. Copyright 2020 Wiley-VCH. Figure e is reprinted with permission from ref 71. Copyright 2021 American Chemical Society. Download figure Download PowerPoint To investigate the relationship between the molecular structure and the photosensitizing performance of AIE agents, four PSs, which were named TPAN, TPAPy, TPANPF6, and TPAPyPF6, composed of the electron-donating triphenylamine and electron-withdrawing azafluorenone and different substituents were designed and synthesized by Tang’s group (Figure 1b).31 The nonionized compounds (TPAN and TPAPy) displayed higher molar absorption coefficients relative to their corresponding ionized counterparts (TPANPF6 and TPAPyPF6). Meanwhile, TPAN exhibited a typical ACQ effect, whereas the other three compounds were all AIE-active as verified by the enhanced fluorescence intensity in the high water fractions of organic solvent/water mixtures. The ionized compounds (TPANPF6 and TPAPyPF6) showed higher ROS generation capacity compared to their nonionized parent, when a general commercial ROS indicator 2′,7′-dichlorodihydro-fluorescein diacetate (H2DCF-DA) that measures many types of ROS activity including type I and type II was employed. However, the singlet oxygen generation ability of TPAPy is higher than that of TPAPyPF6, indicating TPAPyPF6 produced both singlet oxygen and free-radical ROS. According to a previous report, enhanced ISC benefits the ROS generation through promoting spin-orbital coupling (SOC) and lowing the energy gaps between the S1 state and T1 state (ΔEST).50,51 These four PSs showed similar SOC through theoretical calculation. Therefore, the ΔEST values should be the key factor to determine the ROS generation efficiency of these four PSs. However, such a theory cannot give a satisfactory explanation for the ROS generation efficiency order of these four PSs. Especially for TPAN, which has a small ΔEST but inefficiently generates ROS. Therefore, other factors such as the large difference in molar absorption coefficient or the aggregation state of PSs should also attribute to the ROS generation efficiency. Scheme 2 | Chemical structure of photothermal AIE agents for PTT. Download figure Download PowerPoint The singlet oxygen generation by type II PSs is the primary species in PDT.47,52 However, its oxygen dependence limits the generation efficiency in the hypoxic disease microenvironment. In fact, the oxygen consumption of the singlet oxygen generation process even aggravates the disease hypoxia and further reduces its treatment efficacy.53–55 Therefore, the design of type I PSs to generate free radicals in an oxygen-independent manner shows the potential to resolve this issue.56–58 The type I ROS, including superoxide radical (O2•−), hydrogen peroxide (H2O2), and OH•, are generated in a cascade reaction via electron transfer after laser irradiation. O2•− is first converted to H2O2 and O2 by intracellular superoxide dismutase (SOD)-mediated disproportionation, and the generated H2O2 is further catalyzed by ferrous ions to form highly cytotoxic OH•, resulting in the successful PDT (Figure 1c).59,60 To explore the molecular engineering strategy to fabricate AIE agents with type I ROS generation ability, Tang et al.33 included anion-π+ structures into the AIE agents to obtain strong ICT characteristics to promote electron transfer from excited AIE agents to adjacent substrates. The electron-rich group in the AIE agent structure could improve the electron density of the triplet excited state, which should facilitate the generation of free radical ROS. Four anion-π+ AIE agents, which were named TBZPy, MTBZPy, TNZPy, and MTNZPy, were prepared (Figure 1d). These AIE agents were composed of three parts: triphenylamine (TPA) or its methoxy-substituted triphenylamine (MTPA) units linking benzo-1,2,3-thiadiazole (BZ) or naphtho[2,3-c][1,2,5]thiadiazole (NZ) moieties as the AIE-active electron donors, styrylpyridine cation as the electron acceptor, and iodide anion and collaborative donors to create electron-rich conditions for providing electrons to excited AIE agents.61 It was found that NZ-based AIE agents generated free radical ROS while TBZPy primarily generated 1O2 species. MTBZPy yielded both 1O2 and free radical ROS due to the enhanced donor effect. Compared with BZ-based AIE agents, the NZ-based structure in AIE agents boosted the ICT intensity, leading to the high free radical ROS generation efficacy. These results demonstrated the importance of the electron-rich anion-π+ structure for the design of AIE agents with type I ROS generation ability. The electron transfer mechanism of type I PSs exists not only in ICT but also in charge transfer between substrates.62–64 In most luminophore systems, photon excitation triggers energy level transition and is dissipated through radiative or nonradiative decay processes. Besides laser irradiation, chemical reaction provides another pathway for subsequently controlling the excitation of the surrounding species.65–67 Photochemical reactions such as photochromism and photocyclization in tetraphenyl ethylene (TPE) and stilbene have been reported.68–70 Under UV light irradiation, stilbene undergoes trans–cis isomerization, which induces subsequent photocyclization of cis-stilbene to form trans-4a,4b-dihydrophenanthrene. However, this unstable structure reverts to cis-stilbene if not trapped. Utilizing oxidative trapping, dihydrophenanthrene is oxidized to irreversibly yield phenanthrene, which is the pivotal step in photocyclization. Therefore, improving the photochemical efficiency of TPE could be used for the design of type I PS. Based on the electron-rich anion-π+ structure with a photochemical reaction feature, Tang et al.71 designed and synthesized an isoquinolinium organic salt derivative with a TPE structure feature, named TIdBO, to investigate the type I ROS generation efficacy (Figure 1e). This AIE agent displayed strong ICT and potential photocyclization reactivity, providing opportunities for electron transfer and improved free radical ROS in prospect. Compared to its similar AIE agent, TIOdB, which possesses photoinduced crystallization with an emission enhancement (PICEE) property, exhibited high photocyclization reactivity in the dispersive state and sufficiently produced type I ROS upon aggregation due to the translocation of the electron-donating methoxy group. To reveal the structure–function relationship in this photochemistry-based type I PS, single crystals of TIdBO were obtained to confirm its molecular structure and conformation. The tetraphenyl ethylene group showed a twisted propeller conformation, leading to less π–π stacking interaction, which could suppress the ACQ effect. Tetrafluoroborate anions were interspersed on different sides of the twisted plane and exhibited a similar effect to avoid emission quenching. TIdBO in phosphate-buffered saline (PBS) solution showed a robust ROS generating capacity under white light irradiation, and only OH• free radicals were detected when using 2,7-dichlorodihydrofluorescein (DCFH), 9,10-anthracenediyl-bis(methylene) dimalonic acid (ABDA), singlet oxygen sensor green (SOSG), dihydro-rhodamine 123 (DHR123), and hydroxyphenyl fluorescein (HPF) as ROS general or special indicators, confirming the efficient free radical ROS generator of TIdBO. However, the ROS generating efficiency of TIdBO in Dulbecco’s modified eagle medium (DMEM) + 10% fetal bovine serum (FBS) mixtures showed the opposite results. The photocyclization was completely inhibited in PBS solution, but obvious in DMEM + FBS mixtures. The photocyclization process was impacted by the excited-state molecular conformational adjustment, which occurred easily in solution or loose aggregates but hardly in tight aggregates because the twisted dihedral angles impeded planarization in photocyclization. Therefore, in the aggregated state such as in PBS solution, TIdBO could not acquire the molecular conformation, which is necessary for the photocyclization process, and thus impels the electron in the excited state to interact with oxygen to dissipate energy, leading to the generation of type I ROS. Various design strategies have been explored to create AIE agents with high ROS generating efficiency.72,73 For example, a strong electron donor–acceptor interaction in the molecular skeleton facilitates ICT, thus leading to the enhanced singlet oxygen generation efficacy.74 Based on these design strategies, Tang et al.74 synthesized several zwitterionic compounds, BITT, BITB, ITT, and ITB, which consist of a dimethylaniline or triphenylamine moiety as the donor, thiophene fragment as a donor and π-bridge, double bond for the π-bridge, and a quaternary ammonium salt unit as acceptor. Here, the strong D–A effect contributed to the separation of highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) distribution and a reduced energy gap for ISC, which critically enhanced the ROS generation. In a similar work, Tang et al.75 designed two AIE agents TTPy and MeTTPy containing a pyridinium unit (as A), double bond (π-bridge), thiophene fragment (D and π-bridge), and triphenylamine segment (D). Twisted conformation of the triphenylamine moiety can enlarge the intermolecular distance, which generally prevents π–π stacking interaction. This aggregation-related character promoted the ISC process, while the enhancement of the D–A strength also contributed to the ROS generating efficacy of AIE agents. Moreover, the D–π–A molecular structure is widely adopted in the design of AIE agents for strong charge transfer and certainly benefits the adjustment of the HOMO and LUMO.50 A new AIE agent, MeO-TPE-indo (MTi), designed according to this strategy, contains an electron donor methoxy group and an acceptor indo moiety modified on the TPE conjugated skeleton and exhibits the effective generation of ROS for PDT.30 The spin-orbit coupling constant (ξST) is an ISC efficiency factor that essentially influences ROS generation.76 However, ξST in traditional organic fluorophores could be adjusted in narrow range. Introducing heavy atoms, such as bromine, into the structure of AIE agents could potentially solve this issue. Tang et al.77 synthesized two red-emissive AIE agents, named TBP-1 and TBP-2, with addition of bromine atoms in the anion-π+ structure. Results demonstrated that charge transfer occurring from the bromine atoms to the π-conjugated core in TBP-1 and TBP-2 could reduce ΔEST and increase energy levels of the excited triplet states, thus achieving efficient ROS generation. AIE agents for PDT applications PDT has been widely applied in the biomedical field due to its noninvasive and controllable characteristic.78,79 Although design strategies for enhancing ROS generation by AIE agents have been well developed, the absence of their disease targeting ability could cause phototoxicity toward normal tissue.80 Recently, in situ synthesis of antitumor drugs inspired a PS design that largely decreases toxicity and specifically targets the PSs to the tumor region.81 Liu et al.82 designed a nanoscale metal–organic framework (nMOF) that carries AIE precursors and utilizes an F127 coating to form precursor-loaded MOF nanoparticles (PMOF NPs) (Figure 2a). A Cu-embedded nMOF, MOF-199, was chosen as the carrier due to the high loading efficiency of PS precursors and catalytic activity of the Cu-based skeleton. TPA-alkyne-2+ and MePy-N3, having negligible photoactivity before coupling, were chosen as the precursors. This nanosystem could specifically generate Cu(I) from glutathione (GSH) reduction of the Cu(II) skeleton in cancerous cells; a subsequently induced in situ click reaction of TPA-alkyne-2+ and MePy-N3 provides photosensitive TPATrzPy-3+, which performed highly efficient ROS generation (Figures 2b and 2c). Moreover, the co-localization of TPATrzPy-3+ and MitoTracker Green under confocal laser scanning microscopy revealed the mitochondria-targeting property of TPATrzPy-3+, which assists the killing of cancer cells (Figure 2d). Thus, an in vivo antitumor experiment was conducted on zebrafish, showing an excellent phototherapy effect via this in situ catalysis strategy (Figure 2e). Figure 2 | (a) Synthetic mechanism of TPATrzPy-3+ in situ and components of PMOF NPs. (b) GSH-induced in situ PS synthesis for PDT. (c) Viability of HeLa cells after 24 h incubation with a range of concentrations of different agents under light irradiation. (d) Confocal laser scanning microscopy (CLSM) images of HeLa cells incubated with precursors or TPATrzPy-3+ for 24 h before staining of commercialized mitotracker for 30 min. (e) The relative tumor volume changes of zebrafish under different treatment. (f) Chemical structure of organelle-targeting AIE agents and schematic illustration of multi-organelle killing PDT. *, **, *** represent different person correlation coefficients (p); *p < 0.05, **p< 0.01, ***p< 0.001. (g) Confocal microscopy images of HeLa cells for co-localization test of different AIE agents with commercialized organelle trackers: (A) TFPy; (B) TFVP; (C) TPE-TFPy; (D) All three AIE agents. (h) Viability of HeLa cells incubated with different concentrations of AIE agents under light irradiation. Figures a–e are reprinted with permission from ref 82. Copyright 2021 Wiley-VCH. Figures f–h are reprinted with permission from ref 83. Copyright 2020 Wiley-VCH. Download figure Download PowerPoint Tang et al.83 put forward an innovative strategy for PDT that combines multiple AIE agents with different targeting abilities to achieve a 1 + 1 + 1 < 3 photosensitizing effect (Figure 2f). Three novel AIE PSs, TFPy, TFVP, and TPE-TFPy, were tailored based on the D–A feature with slight adjustments, and could specifically endow mitochondria, cell membrane, and lysosome target ability, respectively, to perform full-scale photodynamic killing of cancer cells. The high efficiency of electrophoretic transmembrane migration and binding affinity of the positively charged pyridinium moiety toward the negatively charged interior of the transmembrane potential of mitochondria contribute to the mitochondria-staining ability of TFPy.84 The high free-energy barrier caused low membrane permeability coefficients of TFVP and led to specific accumulation of TFVP in the cell membrane.85 TPE-TFPy generally formed nano-sized aggregates due to high hydrophobicity; whereas in situ aggregates targeted lysosomes through endocytosis. The colocalization of these three AIE agents with the commercial organelle fluorescent probes including MitoTracker Green, CellMask Green, and LysoTracker Green, respectively, indicate the high targeting ability of AIE agents to the respective organelle (Figure 2g). Thus, the three-in-one group which was comprised of one-third concentration of each AIE agent showed the best PDT effect in vitro and in vivo experiments compared to the single AIE agent at the same total concentration, indicating 1 + 1 + 1 < 3 synergistic PDT via three-pronged attack of tumor cells (Figure 2h). PDT used in antibacterial treatment has also been explored to discriminate Gram-positive (G(+)) and Gram-negative (G(−)) bacteria or to conquer drug tolerance caused by antibiotic drug abuse.86,87 To investigate the relationship between antibacterial efficiency and chemical structure of AIE agents, Tang et al.77 designed two red-emissive AIE agents (TBP-1 and TBP-2) with the same luminogenic core but a different number of positive charges . The importance of the number of positive charges of AIE agents on the antibacterial performance was found by revealing the different behavior of TBP-1 and TBP-2 under incubation with G(+)and G(−) bacteria. Both TBP-1 and TBP-2 exhibited dark toxicity to G(+) bacteria and obvious ROS activation under light irradiation (Figure 3a). However, TBP-1 barely killed G(−) bacteria either in dark or under light irradiation, whereas TBP-2 showed much higher phototoxicity toward G(−) bacteria (Figure 3b). Further investigation into the underlying mechanism of antibacterial activity by TBP-2 under laser irradiation found that both TBP-1 and TBP-2 accumulated in the bacteria wall and cytoplasm of G(+) bacteria, demonstrating the strong interactions between AIE agents and the G(+) bacteria lead to effective dark toxicity (Figure 3c). However, TBP-2 showed stronger accumulation in the bacteria wall of G(−) bacteria, indicating that TBP-2 interacts better with bacteria G(−) compared to TBP-1. The difference in accumulation is probably due to the difference in the number of positive charges of the AIE agents (Figure 3d). When the TBP-2-incubated G(−) bacteria was treated with Mg2+, obvious fluorescence quenching of TBP-2 was found, indicating the interactions between lipopolysaccharide (LPS) and TBP-2 were blocked by the divalent cations (Figure 3e). This phenomenon revealed that sufficiently positive-charged TBP-2 could interact more strongly with the negatively charged LPS on the outer membrane of G(−) bacteria and compete with the divalent cations (Ca2+ or Mg2+) that are bonded to stabilize the LPS structure. This process may cause cracks in the permeability barrier, benefiting the penetration of TBP-2 into the periplasmic space of G(−) bacteria for effectively destroying the biomolecules of G(−) bacteria. Moreover, TBP-1 and TBP-2 showed selective photoinactivation of G(+) and G(−) bacteria, respectively, over mammalian cells. Figure 3 | Survival rate of (a) G(+) and (b) G(−) bacteria under incubation with various concentrations of TBP-1 and TBP-2 in the dark or with light irradiation. Confocal fluorescent images of (c) Staphylococcus epidermidis (G(+)) and (d) Escherichia coli (G(−)) after incubation with (A1–A4, C1–C4) TBP-1 or (B1–B4, D1–D4) TBP-2 and Hoechst 33343 for 10 min. (e) Photoluminescence (PL) intensity change of TBP-1 or TBP-2 with or without E. coli G(−) bacteria in PBS upon increasing Mg2+ concentration. Reprinted with permission from ref 77. Copyright 2020 WILEY-VCH. Download figure Download PowerPoint Recently, antibiotic drug abuse has become an intractable problem that directly induces tolerance of antibiotics in the bacterial population.88 A typical antibiotic, vancomycin (Van), possesses a pesticide effect on G(+) bacteria by specific binding affinity to the peptidoglycan sequence N-acyl-d-Ala-d-Ala presented on G(+) bacterial cell walls. However, the occurrence of Van-resistant Enterococcus (VRE), having a largely decreased binding affinity for Van, impedes the therapeutic effect on infection problems.89 Synthesis of dimer or oligomer types of Van is an alternative method to maintain the binding ability.90 Liu et al.91 reported a novel AIE agent conjugated with two Van groups for antibacterial treatment, named AIE-2Van. AIE-2Van showed a high binding affinity toward G(+) bacteria and retained the binding affinity toward VRE bacteria. Under restricted concentration, AIE-2Van performed satisfactory ROS generation when incubated with VRE bacteria. Therefore, although AIE-2Van showed low killing efficiencies on VRE bacteria in the dark due to the resistance of VRE bacteria to Van, the maintained binding ability of AIE-2Van to VRE bacteria boosted its antibacterial effect through ROS generation under light irradiation, indicating the great potential for PS-assisted antibacterial therapy against antiobitc-tolerant bacteria. AIE Agents with Photothermal Conversion Performances Design strategies to enhance the photothermal conversion efficiency of AIE agents Under laser irradiation, the nonradiative decay of excited-state energies is inevitable due to natural vibration and rotation.92 Utilizing dissipated energy as the thermal effect for PTT has been well investigated in the biomedical field. Various structure-dependent design strategies have been explored for boosting the nonradiative relaxation of photothermal agents.93,94 For instance, Pu et al.95 quenched the fluorescence of semiconducting polymer nanoparticles by intraparticle photoinduced electron transfer to achieve heat generation. Lee et al.96 modified the semiconducting polymer chains with light-harvesting groups to increase the