Self-Adaptive Photodynamic-to-Photothermal Switch for Smart Antitumor Photoimmunotherapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.

Precise molecular engineering for the preparation of pyridinium photosensitizers with efficient ROS generation and photothermal conversion.

Organic photosensitizers (PSs) with aggregation-induced emission properties have great development potential in the integrated application of multi-mode diagnosis and treatment of photodynamic therapy (PDT) and photothermal therapy (PTT). However, preparing high-quality PSs with both optical and biological properties, high reactive oxygen species (ROS) and photothermal conversion ability are undoubtedly a great challenge. In this work, a series of pyridinium AIE PSs modified with benzophenone have been synthesized. A wide wavelength range of fluorescent materials was obtained by changing the conjugation and donor-acceptor strength. TPAPs5 has a significant advantage over similar compounds, and we have also identified the causes of high ROS generation and high photothermal conversion in terms of natural transition orbitals, excited state energy levels, ground-excited state configuration differences and recombination energy. Interestingly, migration of target sites was also found in biological imaging experiments, which also provided ideas for the design of double-targeted fluorescent probes. Therefore, the present work proposed an effective molecular design strategy for synergistic PDT and PTT therapy.

Near-Infrared Conjugated Polymers Containing Thermally Activated Delayed Fluorescence Units Enable Enhanced Photothermal Therapy.

Photothermal therapy (PTT) using near-infrared (NIR) conjugated polymers as photosensitizers has exhibited enormous potential for tumor treatment. However, most NIR conjugated polymers have poor therapeutic efficacy due to their faint absorbance in the NIR region and low photothermal conversion efficiency (PCE). Herein, a valuable strategy for designing NIR polymeric photosensitizer PEKBs with an enhanced PCE accompanied by strong NIR absorbance is proposed by means of inserting TPA-AQ as a thermally activated delayed fluorescence unit into a polymeric backbone. In these PEKBs, PEKB-244 with the appropriate molar content of the TPA-AQ unit displays the strongest NIR absorbance and the highest PCE of 64.5%. Theoretical calculation results demonstrate that the TPA-AQ unit in the polymeric backbone can modulate the intramolecular charge transfer effects and the excited energy decay routes for generating higher heat. The prepared nanoparticles (PEKB-244 NPs) exhibit remarkable photothermal conversion capacities and great biocompatibility in aqueous solutions. Moreover, PEKB-244 NPs also show outstanding photothermal stability, displaying negligible changes in the absorbance within 808 nm irradiation of 1 h (800 mW cm-2). Both in vitro and in vivo experimental results further indicate that PEKB-244 NPs can substantially kill cancer cells under NIR laser irradiation. We anticipate that this novel molecular design strategy can be employed to develop excellent NIR photosensitizers for cancer photothermal therapy.

Molecular engineering to enhance the reactive oxygen species generation of AIEgens and exploration of their versatile applications.

Fluorescent dyes with aggregation-induced emission (AIE) characteristics have shown potential applications in the fields of biological imaging, photodynamic therapy and photothermal therapy, in which photosensitizers (PSs) play a crucial role. However, how to design high-quality PSs with high reactive oxygen species (ROS) generation efficiency remains unclear. In this contribution, an effective molecular design strategy to improve the ROS generation efficiency of AIE PSs was proposed. A series of tetraphenylethylene derivatives containing the pyridine ring or pyridinium with different substituents were designed and synthesized. All the molecules were weakly emissive when molecularly dissolved in solution but displayed intense emission upon aggregation, demonstrating a phenomenon of AIE characteristic. Pyridinium molecules could be used as visualization agents to specifically stain the mitochondria in living cells, while most of the molecules failed to generate ROS upon white light irradiation. In contrast, TPE-Pys-BP containing benzophenone produced ˙OH and 1O2 efficiently in the presence of light due to its large spin-orbit coupling constant to promote efficient intersystem crossing. Such a property allowed TPE-Pys-BP to serve as a PS to kill cancer cells using photodynamic therapy. TPE-Pys-BP also exhibited mechanochromic luminescence (ML), and its emission could be reversibly switched between two distinct colors through repeated grinding and fuming processes. A security paper was fabricated using the ML properties of TPE-Pys-BP.

NIR light-driven pure organic Janus-like nanoparticles for thermophoresis-enhanced photothermal therapy.

Photothermal therapy (PTT) represents a promising noninvasive tumor therapeutic modality, but the current strategies for enhancing photothermal effect have been mainly based on promoting thermal relaxation or suppressing radiative dissipation process of excited energy, leaving little room for further improvement in photothermal effect. Herein, as a proof of concept, we report the thermophoresis-enhanced photothermal effect with pure organic Janus-like nanoparticles (Janus-like NPs) for PTT. The Janus-like NPs are eccentrically loaded with compactly J-aggregated photothermal molecules (DMA-BDTO), which show red-shifted absorption wavelength and inhibited radiative decay as compared to individual molecules. Under NIR irradiation, the asymmetric heat generation at particle surface endows Janus-like NPs the active thermophoresis, which further increases collisions and converts kinetic energy into thermal energy, and Janus-like NPs exhibit significantly elevated temperature as compared to conventional NPs with homogenously distributed DMA-BDTO. Both in vitro and in vivo results confirm such thermophoresis-enhanced photothermal effect for improved PTT. Our new strategy of thermophoresis-enhanced photothermal effect shall open new insights for improving photothermal-related tumor therapy.

Combining PD-L1 blockade with immunogenic cell death induced by AIE photosensitizer to improve antitumor immunity.

Immunogenic cell death (ICD) is considered an effective death mode to trigger immune response. However, the currently available efficient ICD inducers are quite limited. Endoplasmic reticulum (ER) stress is known as the precursor of ICD, which can be directly triggered by reactive oxygen species in situ. Herein, a novel photosensitizer (α-Th-TPA-PIO) based on phosphindole oxide, featuring aggregation-induced emission (AIE) is designed and prepared, which possesses good ability of hydroxyl radicals (HO•) generation. Besides, α-Th-TPA-PIO can selectively accumulate in ER and trigger ER stress under white light irradiation, further leading to effective ICD. Combining with anti-programmed death-ligand 1 (anti-PD-L1), the synergistic effect of photodynamic therapy (PDT) and immune checkpoint blockade can achieve a significantly enhanced inhibition effect on the growth of tumors and simultaneously provoke a systemic antitumor immune response. Notably, by adopting this therapeutic strategy to bilateral and metastatic tumor models, the growth of both primary and distant subcutaneous tumors can be successfully suppressed, and metastatic tumor can also be inhibited to some degree. Taken together, this work not only provides a novel ICD photoinducer based on PDT, but also brings about a useful immunomodulatory strategy to realize superior antitumor effect.

A photoactivatable theranostic probe for simultaneous oxidative stress-triggered multi-color cellular imaging and photodynamic therapy.

Simultaneous in situ monitoring critical organelles upon oxidative stress and implementing therapeutics utilizing oxidative stress are of vital importance and remain challenging task. Herein, we rationally design and facilely synthesized a photoactivatable fluorescent probe bearing 1,4-dihydropyridine moiety with aggregation-induced emission (AIE) tendency, namely TPA-DHPy, which can rapidly transform into its pyridine counterpart TPA-Py via photo-oxidative dehydrogenation showing strong polarity sensitivity and largely red-shifted emission. TPA-DHPy- and TPA-Py-based type I/type II photosensitization is able to effectively generate reactive oxygen species to induce in situ oxidative stress under white light irradiation. TPA-DHPy can be taken up by cancer cells, and gradually light up lipid droplets (LDs) and endoplasmic reticulum (ER) during photoactivatable process, as well as in situ monitoring difference and alteration of their microenvironment upon oxidative stress by means of multi-color fluorescence imaging in lambda mode. Furthermore, the in situ generated TPA-Py is capable of further destroying the functions of LDs and ER with prolonging the irradiation time, and remarkably inhibiting tumor growth under white light irradiation by the way of photodynamic therapy. This study thus offers useful insights into designing a new generation of theranostic agents towards imaging-guided precise cancer therapy.

Precisely Detecting the Telomerase Activities by an AIEgen Probe with Dual Signal Outputs after Cell-Cycle Synchronization.

By maintaining the telomere lengths, telomerase can make the tumor cells avoid the apoptosis, thus, achieving the cell immortalization. In the past, a series of telomerase detection systems have been developed through utilizing the unique characteristic of telomerase extended primer. However, fluctuation of telomerase activity, along with the cell cycle progression, leads to ambiguous detection results. Here, we reported a dual signal output detection strategy based on cell-cycle synchronization for precisely detecting telomerase activities by using a new AIEgen probe SSNB. Experimental and simulating calculation results demonstrated that positively charged SSNB could interact with DNA through the electrostatic interaction and π-π interaction, as well as the hydrogen bonds. The aggregation of SSNB caused by the extended template strand primer (TP) could be observed in tumor cells, thus, indicating the telomerase activity in various cell lines. Furthermore, after cell cycle synchronization, it was found that the telomerase activity in the S phase was the highest, no matter from the fluorescence intensity or the ROS generation situation. Dual signal outputs of SSNB verified the significance and necessity of cell-cycle synchronization detection for telomerase activity. This strategy could open a new window for the biotargets of which activity is variational in time dimension.

Oxygen Quenching-Resistant Nanoaggregates with Aggregation-Induced Delayed Fluorescence for Time-Resolved Mapping of Intracellular Microviscosity.

Microviscosity is a fundamental parameter in the biophysics of life science and governs numerous cellular processes. Thus, the development of real-time quantitative monitoring of microviscosity inside cells is important. The traditional probes for detecting microviscosity via time-resolved luminescence imaging (TRLI) are generally disturbed by autofluorescence or surrounding oxygen in cells. Herein, we developed loose packing nanoaggregates with aggregation-induced delayed fluorescence (FKP-POA and FKP-PTA) and free from the effect of oxygen and autofluorescence for viscosity mapping via TRLI. The feasibility of FKP-PTA nanoparticles (NPs) for microviscosity mapping through TRLI was demonstrated by monitoring the variation of microviscosity inside HepG2 cancer cells, which demonstrated a value change from 14.9 cP to 216.9 cP during the apoptosis. This indicates that FKP-PTA NP can be used as a probe for cellular microviscosity mapping to help people to understand the physiologically dynamic microenvironment. The present results are expected to promote the advancement of diagnostic and therapeutic methods to cope with related diseases.

Aggregation-induced emission luminogens for image-guided surgery in non-human primates.

During the past two decades, aggregation-induced emission luminogens (AIEgens) have been intensively exploited for biological and biomedical applications. Although a series of investigations have been performed in non-primate animal models, there is few pilot studies in non-human primate animal models, strongly hindering the clinical translation of AIE luminogens (AIEgens). Herein, we present a systemic and multifaceted demonstration of an optical imaging-guided surgical operation via AIEgens from small animals (e.g., mice and rabbits) to rhesus macaque, the typical non-human primate animal model. Specifically, the folic conjugated-AIE luminogen (folic-AIEgen) generates strong and stable fluorescence for the detection and surgical excision of sentinel lymph nodes (SLNs). Moreover, with the superior tumor/normal tissue ratio and rapid tumor accumulation, folic-AIEgen successfully images and guides the precise resection of invisible cancerous metastases. Taken together, the presented strategies of folic-AIEgen based fluorescence intraoperative imaging and visualization-guided surgery show potential for clinical applications.

9,10-Phenanthrenequinone: A Promising Kernel to Develop Multifunctional Antitumor Systems for Efficient Type I Photodynamic and Photothermal Synergistic Therapy.

Synergistic phototherapy provides a promising strategy to conquer the hypoxia and heterogeneity of tumors and realize a better therapeutic effect than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). The development of efficient multifunctional organic phototheranostic systems still remains a challenging task. Herein, 9,10-phenanthrenequinone (PQ) with strong electron-withdrawing ability is conjugated with the rotor-type electron-donating triphenylamine derivatives to create a series of tailor-made photosensitizers. The highly efficient Type I reactive oxygen species generation and outstanding photothermal conversion capacity are tactfully integrated into these PQ-cored photosensitizers. The underlying photophysical and photochemical mechanisms of the combined photothermal and Type I photodynamic effects are deciphered by experimental and theoretical methods and are closely associated with the active intramolecular bond stretching vibration, facilitated intersystem crossing, and specific redox cycling activity of the PQ core. Both in vitro and in vivo evaluations demonstrate that the nanoagents fabricated by these PQ-based photosensitizers are excellent candidates for Type I photodynamic and photothermal combined antitumor therapy. This study thus broadens the horizon for the development of high-performance PTT/Type I PDT nanoagents for synergistic phototheranostic treatments.

Improving Image-Guided Surgical and Immunological Tumor Treatment Efficacy by Photothermal and Photodynamic Therapies Based on a Multifunctional NIR AIEgen.

Multimodal therapy is attracting increasing attention to improve tumor treatment efficacy, but generally requires various complicated ingredients combined within one theranostic system to achieve multiple functions. Herein, a multifunctional theranostic nanoplatform based on a single aggregation-induced-emission luminogen (AIEgen), DDTB, is designed to integrate near-infrared (NIR) fluorescence, photothermal, photodynamic, and immunological effects. Intravenously injected AIEgen-based nanoparticles can efficiently accumulate in tumors with NIR fluorescence to provide preoperative diagnosis. Most of the tumors are excised under intraoperative fluorescence navigation, whereafter, some microscopic residual tumors are completely ablated by photodynamic and photothermal therapies for maximally killing the tumor cells and tissues. Up to 90% of the survival rate can be achieved by this synergistic image-guided surgery and photodynamic and photothermal therapies. Importantly, the nanoparticles-mediated photothermal/photodynamic therapy plus programmed death-ligand 1 antibody significantly induce tumor elimination by enhancing the effect of immunotherapy. This theranostic strategy on the basis of a single AIEgen significantly improves the survival of cancer mice with maximized therapeutic outcomes, and holds great promise for clinical cancer treatment.

Nitrogen-Rich Tetraphenylethene-Based Luminescent Metal-Organic Framework for Efficient Detection of Carcinogens.

The introduction of nitrogen-rich functional groups into a luminescent metal-organic framework (LMOF) can enhance its fluorescent sensing ability. In this work, we designed and synthesized a triazole-containing tetracarboxyl-substituted tetraphenylethene (TPE) ligand, tetrakis[4-(4-carboxyphenyl)(1H-1,2,3-triazol-4,1-diyl)phenyl]ethene (H4TCPTAPE), featuring a prominent aggregation-induced emission (AIE). A highly porous TPE-based LMOF [Zn3(TCPTAPE)(H2O)2(OH)2] (1) with large pores was successfully obtained via solvothermal assembly of the H4TCPTAPE ligand and Zn(II) ions, which showed a high fluorescence quantum yield of 54%. The activated 1 could selectively and sensitively detect aristolochic acid I with a high fluorescence quenching efficiency of 96% and a low detection limit of 1.02 µM, indicating that it has a potential application as a luminescence-based chemical sensor for carcinogens.

Self-Guiding Polymeric Prodrug Micelles with Two Aggregation-Induced Emission Photosensitizers for Enhanced Chemo-Photodynamic Therapy.

Nowadays, aggregation-induced emission luminogens (AIEgens) with reactive oxygen species (ROS) generating ability have been used as photosensitizers for imaging guided photodynamic therapy (PDT). To achieve enhanced antitumor outcomes, combining AIEgens-based PDT with chemotherapy is an efficient strategy. However, the therapeutic efficiency is hampered by the limited cellular uptake efficiency and the appropriate light irradiation occasion. In this paper, a self-guiding polymeric micelle (TB@PMPT) composed of two AIE photosensitizers and a reduction-sensitive paclitaxel prodrug (PTX-SS-N3) was established for enhanced chemo-photodynamic therapy by a dual-stage light irradiation strategy. When the micelles were accumulated in tumor tissues, the first light irradiation (L1, 6 min) was utilized to facilitate cellular uptake by "photochemical internalization" (PCI). Then, the intracellular glutathione (GSH) would induce the PTX release, micelles disassembly and the aggregation state change of AIEgens. The fluorescence signal change of two AIEgens-based ratiometric fluorescent probe could not only precisely guide the second light irradiation (L2, 18 min) for sufficient ROS production, but also monitor the nonfluorescent drug PTX release in turn. Both in vivo and in vitro studies demonstrated that the dual-stage light irradiation strategy employed for TB@PMPT micelles exhibited a superior therapeutic effect over only 24 min continuous light irradiation.

Modular Peptide Probe for Pre/Intra/Postoperative Therapeutic to Reduce Recurrence in Ovarian Cancer.

Even with optimal surgery, 80% of patients with ovarian cancer will have recurrence. Adjuvant therapy can reduce the recurrence of tumors; however, the therapeutic effect is still not prominent. Herein, we designed a modular peptide probe (TCDTMP), which can be self-assembled into nanoparticles (NPs) by loading in miR-145-5p or VEGF-siRNA. In vivo, (1) preoperative administration of TCDTMP/miR-145-5p ensured that NPs were adequately accumulated in tumors through active targeting and increased the expression of miR-145-5p in tumors, thereby inducing tumor cell apoptosis. (2) Intraoperatively, most of the tumors were removed, while the microscopic residual tumors were largely eliminated by TCDTMP/miR-145-5p-mediated photodynamic therapy (PDT). (3) Postoperatively, TCDTMP/VEGF-siRNA were given for antiangiogenesis therapy, thus delaying the recurrence of tumors. This treatment was named a preoperative (TCDTMP/miR-145-5p)||intraoperative (surgery and PDT)||postoperative (TCDTMP/VEGF-siRNA) therapeutic system and abbreviated as the PIP therapeutic system, which reduced the recurrence of ovarian cancer in subcutaneous tumor models, intraperitoneal metastasis models, and patient-derived tumor xenograft models. Our findings provide a therapeutic system based on modular peptide probes to reduce the recurrence of ovarian cancer after surgery, which provides a perspective for the surgical management of ovarian cancer.

Bright Aggregation-Induced Emission Nanoparticles for Two-Photon Imaging and Localized Compound Therapy of Cancers.

Photodynamic therapy (PDT), a noninvasive therapeutic strategy for cancer treatment, which always suffers from the low reactive oxygen species (ROS) yield of traditional organic dyes. Herein, we present lipid-encapsulated aggregation-induced emission nanoparticles (AIE NPs) that have a high quantum yield (23%) and a maximum two-photon absorption (TPA) cross-section of 560 GM irradiated by near-infrared light (800 nm). The AIE NPs can serve as imaging agents for spatiotemporal imaging of tumor tissues with a penetration depth up to 505 µm on mice melanoma model. Importantly, the AIE NPs can simultaneously generate singlet oxygen (1O2) and highly toxic hydroxyl radicals (•OH) upon irradiation with 800 nm irradiation for photodynamic tumor ablation. In addition, the AIE NPs can be effectively cleared from the mouse body after the imaging and therapy. This study provides a strategy to develop theranostic agents for cancer image-guided PDT with high brightness, superior photostability, and high biosafety.

Tumor-Triggered Disassembly of a Multiple-Agent-Therapy Probe for Efficient Cellular Internalization.

Integration of multiple agent therapy (MAT) into one probe is promising for improving therapeutic efficiency for cancer treatment. However, MAT probe, if entering the cell as a whole, may not be optimal for each therapeutic agent (with different physicochemical properties), to achieve their best performance, hindering strategy optimization. A peptide-conjugated-AIEgen (FC-PyTPA) is presented: upon loading with siRNA, it self-assembles into FCsiRNA -PyTPA. When approaching the region near tumor cells, FCsiRNA -PyTPA responds to extracellular MMP-2 and is cleaved into FCsiRNA and PyTPA. The former enters cells mainly by macropinocytosis and the latter is internalized into cells mainly through caveolae-mediated endocytosis. This two-part strategy greatly improves the internalization efficiency of each individual therapeutic agent. Inside the cell, self-assembly of nanofiber precursor F, gene interference of CsiRNA , and ROS production of PyTPA are activated to inhibit tumor growth.

Nanococktail Based on AIEgens and Semiconducting Polymers: A Single Laser Excited Image-Guided Dual Photothermal Therapy.

Semiconducting polymers (SPs)-based dual photothermal therapy (PTT) obtained better therapeutic effect than single PTT due to its higher photothermal conversion efficiency. However, most dual PTT need to use two lasers for heat generation, which brings about inconvenience and limitation to the experimental operations. Herein, we report the development of "nanococktail" nanomaterials (DTPR) with 808 nm-activated image-guided dual photothermal properties for optimized cancer therapy. Methods: In this work, we co-encapsulated AIEgens (TPA-BDTO, T) and SPs (PDPPP, P) by using maleimide terminated amphiphilic polymer (DSPE-PEG2000-Mal, D), then further conjugated the targeting ligands (RGD, R) through "click" reaction. Finally, such dual PTT nanococktail (termed as DTPR) was constructed. Results: Once DTPR upon irradiation with 808 nm laser, near-infrared fluorescence from T could be partially converted into thermal energy through fluorescence resonance energy transfer (FRET) between T and P, coupling with the original heat energy generated by the photothermal agent P itself, thus resulting in image-guided dual PTT. The photothermal conversion efficiency of DTPR reached 60.3% (dual PTT), much higher as compared to its inherent photothermal effect of only 31.5% (single PTT), which was further proved by the more severe photothermal ablation in vitro and in vivo upon 808 nm laser irradiation. Conclusion: Such smart "nanococktail" nanomaterials could be recognized as a promising photothermal nanotheranostics for image-guided cancer treatment.

Type I photosensitizers based on phosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress.

Photodynamic therapy (PDT) is considered a pioneering and effective modality for cancer treatment, but it is still facing challenges of hypoxic tumors. Recently, Type I PDT, as an effective strategy to address this issue, has drawn considerable attention. Few reports are available on the capability for Type I reactive oxygen species (ROS) generation of purely organic photosensitizers (PSs). Herein, we report two new Type I PSs, α-TPA-PIO and ß-TPA-PIO, from phosphindole oxide-based isomers with efficient Type I ROS generation abilities. A detailed study on photophysical and photochemical mechanisms is conducted to shed light on the molecular design of PSs based on the Type I mechanism. The in vitro results demonstrate that these two PSs can selectively accumulate in a neutral lipid region, particularly in the endoplasmic reticulum (ER), of cells and efficiently induce ER-stress mediated apoptosis and autophagy in PDT. In vivo models indicate that ß-TPA-PIO successfully achieves remarkable tumor ablation. The ROS-based ER stress triggered by ß-TPA-PIO-mediated PDT has high potential as a precursor of the immunostimulatory effect for immunotherapy. This work presents a comprehensive protocol for Type I-based purely organic PSs and highlights the significance of considering the working mechanism in the design of PSs for the optimization of cancer treatment protocols.

Efficient Near-Infrared Photosensitizer with Aggregation-Induced Emission for Imaging-Guided Photodynamic Therapy in Multiple Xenograft Tumor Models.

Photodynamic therapy (PDT) strategy has been widely used in tumor treatment, and the reagents for reactive oxygen species (ROS) play a crucial role. Herein, we develop a fluorogen (TTB) containing an electron-accepting benzo[1,2-b:4,5-b']dithiophene 1,1,5,5-tetraoxide core and electron-donating 4,4'-(2,2-diphenylethene-1,1-diyl)bis(N,N-diphenylaniline) groups for image-guided targeting PDT application. TTB exhibits a prominent aggregation-induced emission (AIE) property with strong near-infrared (NIR) fluorescence in aggregates and is capable of efficiently generating ROS of O2•- and 1O2 under white light irradiation. The nanoparticles (RGD-4R-MPD/TTB NPs) with NIR emission (∼730 nm), high photostability, and low dark cytotoxicity are fabricated by encapsulating TTB within polymeric matrix and then modified with RGD-4R peptide. They show excellent performance in targeting PDT treatment of PC3, HeLa, and SKOV-3 cancer cells in vitro. The investigations on pharmacokinetics, biodistribution, and long-term tracing in vivo reveal that RGD-4R-MPD/TTB NPs can selectively accumulate in tumors for real-time, long-term image-guided PDT treatment. The RGD-4R-MPD/TTB NPs-mediated PDT in multiple xenograft tumor models disclose that the growth of cervical, prostate, and ovarian cancers in mice can be effectively inhibited. These results demonstrate that the reagents employing NIR fluorogen TTB as a photosensitizer could be promising candidates for in vivo image-guided PDT treatments of tumors.