Regulating Charge Transfer in Cyanine Dyes: A Universal Methodology for Enhancing Cancer Phototherapeutic Efficacy.

ConspectusDue to the advantages of spatiotemporal selectivity and inherent noninvasiveness, cancer phototherapy, which includes both photodynamic therapy (PDT) and photothermal therapy (PTT), has garnered significant attention in recent years as a promising cancer treatment. Despite the commendable progress in this field, persistent challenges remain. In PDT, limitations in dyes manifest as low intersystem crossing (ISC) efficiency and oxygen-dependent photoactivity, resulting in unsatisfactory performance, particularly under hypoxic conditions. Similarly, PTT encounters consistent insufficiencies in the photothermal conversion efficiency (PCE) of dyes. Additionally, the suboptimal phototherapeutic efficacy often exhibits a limited immune response. These factors collectively impose significant constraints on phototherapy in oncological applications, leading to limited tumor inhibition, tumor recurrence, and even metastasis.Unlike strategies that rely on external assistance with complicated systems, manipulating excited-state deactivation pathways in biocompatible dyes offers a universal way to systematically address these challenges. Our group has devoted considerable effort to achieving this goal. In this Account, we present and discuss our journey in optimizing excited-state energy-release pathways through regulating molecular charge transfer based on cyanine dyes, which are renowned for their exceptional photophysical properties and harmonious biocompatibility. The investigation begins with the introduction of amino groups in the meso position of a heptamethine cyanine dye, where the intramolecular charge transfer (ICT) effect causes a significant enlargement of the Stokes shift. Subsequently, ICT induced by introducing functional electron-deficient groups in cyanines is found to decrease the overlap of electron distribution or narrow the energy gaps of molecular frontier orbitals. Such modifications result in a reduction of the energy gaps between singlet and triplet states or an improvement in internal conversion, ultimately promoting phototherapy efficacy in both primary and distant tumors. Furthermore, with the intensification of the charge transfer effect aided by light, photoinduced intramolecular electron transfer occurs in some cyanines, leading to complete charge separation in the excited state. This process enhances the transition to the ground or triplet states, improving tumor phototherapy and inhibiting metastasis by increasing the PCE or the yield of reactive oxygen species, respectively. Shifting focus from intramolecular to intermolecular interactions, we successfully constructed and explored cyanines based on intermolecular charge transfer. These dyes, with excited-state dynamics mimicking natural photosynthesis, generate radicals and facilitate oxygen-independent hypoxic tumor PDT. Finally, we outlined the existing challenges and future directions for optimizing phototherapeutic efficacy by regulating molecular charge transfer. This Account provides molecular-level insights into improving phototherapeutic performance, offering valuable perspectives, and inspiring the development of functional dyes in other application fields.

Light-Driven Mitochondrion-to-Nucleus DNA Cascade Fluorescence Imaging and Enhanced Cancer Cell Photoablation.

Nucleic acids are mainly found in the mitochondria and nuclei of cells. Detecting nucleic acids in the mitochondrion and nucleus in cascade mode is crucial for understanding diverse biological processes. This study introduces a novel nucleic acid-based fluorescent styrene dye (SPP) that exhibits light-driven cascade migration from the mitochondrion to the nucleus. By introducing N-arylpyridine on one side of the styrene dye skeleton and a bis(2-ethylsulfanyl-ethy)-amino unit on the other side, we found that SPP exhibits excellent DNA specificity (16-fold, FDNA/Ffree) and a stronger binding force to nuclear DNA (-5.09 kcal/mol) than to mitochondrial DNA (-2.59 kcal/mol). SPP initially accumulates in the mitochondrion and then migrates to the nucleus within 10 s under light irradiation. By tracking the damage to nucleic acids in apoptotic cells, SPP allows the successful visualization of the differences between apoptosis and ferroptosis. Finally, a triphenylamine segment with photodynamic effects was incorporated into SPP to form a photosensitizer (MTPA-SPP), which targets the mitochondria for photosensitization and then migrates to the nucleus under light irradiation for enhanced photodynamic cancer cell treatment. This innovative nucleic acid-based fluorescent molecule with light-triggered mitochondrion-to-nucleus migration ability provides a feasible approach for the in situ identification of nucleic acids, monitoring of subcellular physiological events, and efficient photodynamic therapy.

Pyrazolone-Protein Interaction Enables Long-Term Retention Staining and Facile Artificial Biorecognition on Cell Membranes.

Cell membrane genetic engineering has been utilized to confer cell membranes with functionalities for diagnostic and therapeutic purposes but concerns over cost and variable modification results. Although nongenetic chemical modification and phospholipid insertion strategies are more convenient, they still face bottlenecks in either biosafety or stability of the modifications. Herein, we show that pyrazolone-bearing molecules can bind to proteins with high stability, which is mainly contributed to by the multiple interactions between pyrazolone and basic amino acids. This new binding model offers a simple and versatile noncovalent approach for cell membrane functionalization. By binding to cell membrane proteins, pyrazolone-bearing dyes enabled precise cell tracking in vitro (>96 h) and in vivo (>21 days) without interfering with the protein function or causing cell death. Furthermore, the convenient anchor of pyrazolone-bearing biotin on cell membranes rendered the biorecognition to avidin, showing the potential for artificially creating cell targetability.

Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

Wavelength-Tuneable Fluorescent Carbon Dots for Nucleic Acid Imaging.

Nucleic acid is one of the most important substances in organisms, and its dynamic changes are closely related to physiological processes. Nucleic acid labeling is conducive to providing important information for the early diagnosis and treatment of pathophysiological processes. Here, we utilized the transfer mechanism between carbon sources and CDs to synthesize wavelength-adjustable N-CDs for the nucleic acid image. Along with the increased graphite nitrogen (from 10.6 to 30.1%) gradually by the precise design of the nitrogen structure in carbon sources (e.g., primary amines, secondary amines, tertiary amines, and liking graphite-nitrogen), the energy gap of CDs reduced, resulting in adjustable wavelength from visible to near-infrared range (from 461 nm/527 nm to 650 nm/676 nm). Furthermore, N-CDs exhibited a selective affinity for nucleic acids, especially RNA. Therefore, N-CDs support an efficient platform for real-time tracking of RNA dynamic changes in cells.

Photoinduced Cuproptosis with Tumor-Specific for Metastasis-Inhibited Cancer Therapy.

Cuproptosis is a novel form of regulated cell death which guarantees to increase the efficacy of existing anticancer treatments that employ traditional apoptotic therapeutics. However, reducing the amount of undesirable Cu ions released in normal tissue and maximizing Cu-induced cuproptosis therapeutic effects at tumor sites are the major challenges. In this study, exploiting the chemical properties of copper ionophores and the tumor microenvironment, a novel method is developed for controlling the valence of copper ions that cause photoinduced cuproptosis in tumor cells. CJS-Cu nanoparticles (NPs) can selectively induce cuproptosis after cascade reactions through H2 O2 -triggered Cu2+ release, photoirradiation-induced superoxide radical (∙O2 - ) generation, and reduction of Cu2+ to Cu+ by ∙O2 - . The generated reactive oxygen species can result in glutathione depletion and iron-sulfur cluster protein damage and further augmented cuproptosis. CJS-Cu NPs effectively suppressed tumor growth and downregulated the expression of metastasis-related proteins, contributing to the complete inhibition of lung metastasis. Ultimately, this study suggests novel avenues for the manipulation of cellular cuproptosis through photochemical reactions.

Near-Infrared Heptamethine Cyanine Photosensitizers with Efficient Singlet Oxygen Generation for Anticancer Photodynamic Therapy.

Near-infrared photosensitizers are valuable tools to improve treatment depth in photodynamic therapy (PDT). However, their low singlet oxygen (1O2) generation ability, indicated by low 1O2 quantum yield, presents a formidable challenge for PDT. To overcome this challenge, the heptamethine cyanine was decorated with biocompatible S (Scy7) and Se (Secy7) atom. We observe that Secy7 exhibits a redshift in the main absorption to ~840 nm and an ultra-efficient 1O2 generation capacity. The emergence of a strong intramolecular charge transfer effect between the Se atom and polymethine chain considerably narrows the energy gap (0.51 eV), and the heavy atom effect of Se strengthens spin-orbit coupling (1.44 cm-1), both of which greatly improved the high triplet state yield (61%), a state that determines the energy transfer to O2. Therefore, Secy7 demonstrated excellent 1O2 generation capacity, which is ~24.5-fold that of indocyanine green, ~8.2-fold that of IR780, and ~1.3-fold that of methylene blue under low-power-density 850 nm irradiation (5 mW cm-2). Secy7 exhibits considerable phototoxicity toward cancer cells buried under 12 mm of tissue. Nanoparticles formed by encapsulating Secy7 within amphiphilic polymers and lecithin, demonstrated promising antitumor and anti-pulmonary metastatic effects, exhibiting remarkable potential for advancing PDT in deep tissues.

BF2-Bridged Azafulvene Dimer-Based 1064 nm Laser-Driven Superior Photothermal Agent for Deep-Seated Tumor Therapy.

Small organic photothermal agents (PTAs) with absorption bands located in the second near-infrared (NIR-II, 1000-1700 nm) window are highly desirable for effectively combating deep-seated tumors. However, the rarely reported NIR-II absorbing PTAs still suffer from a low molar extinction coefficient (MEC, ϵ), inadequate chemostability and photostability, as well as the high light power density required during the therapeutic process. Herein, we developed a series of boron difluoride bridged azafulvene dimer acceptor-integrated small organic PTAs. The B-N coordination bonds in the π-conjugated azafulvene dimer backbone endow it the strong electron-withdrawing ability, facilitating the vigorous donor-acceptor-donor (D-A-D) structure PTAs with NIR-II absorption. Notably, the PTA namely OTTBF shows high MEC (7.21×104 M-1 cm-1), ultrahigh chemo- and photo-stability. After encapsulated into water-dispersible nanoparticles, OTTBF NPs can achieve remarkable photothermal conversion effect under 1064 nm irradiation with a light density as low as 0.7 W cm-2, which is the lowest reported NIR-II light power used in PTT process as we know. Furthermore, OTTBF NPs have been successfully applied for in vitro and in vivo deep-seated cancer treatments under 1064 nm laser. This study provides an insight into the future exploration of versatile D-A-D structured NIR-II absorption organic PTAs for biomedical applications.

Red-Light Triggered H-Abstraction Photoinitiators for the Efficient Oxygen-Independent Therapy of Hypoxic Tumors.

The clinical application of photodynamic therapy (PDT) is limited by oxygen-dependence and side effects caused by photosensitizer residues. Photoinitiators based on the H-abstraction reaction can address these challenges because they can generate alkyl radical-killing cells independently of oxygen and undergo rapid bleaching following H-abstraction. Nonetheless, the development of photoinitiators for PDT has been impeded by the absence of effective design strategies. Herein, we have developed aryl-ketone substituted cyanine (ACy-R), the first red-light triggered H-abstraction photoinitiators for hypoxic cancer therapy. These ACy-R molecules inherited the near-infrared absorption of cyanine dye, and aryl-ketone modification imparted H-abstraction capability. Experimental and quantum calculations revealed that modifying the electron-withdrawing groups of the aryl (e.g., ACy-5F) improved the contribution of the O atom to the photon excitation process promoting intersystem crossing and H-abstraction ability. Particularly, ACy-5F rapidly penetrated cells and enriched in the endoplasmic reticulum. Even under severe hypoxia, ACy-5F initiated red-light induced H-abstraction with intracellular biomolecules, inducing necroptosis and ferroptosis. Moreover, ACy-5F was degraded after H-abstraction, thus avoiding the side effects of long-term phototoxicity after therapy. This study not only provides a crucial molecular tool for hypoxic tumors therapy, but also presents a promising strategy for the development of multifunctional photosensitizers and photoinitiators.

Carrier-Free ATP-Activated Nanoparticles for Combined Photodynamic Therapy and Chemotherapy under Near-Infrared Light.

The combination of photodynamic therapy (PDT) and chemotherapy (chemo-photodynamic therapy) for enhancing cancer therapeutic efficiency has attracted tremendous attention in the recent years. However, limitations, such as low local concentration, non-suitable treatment light source, and uncontrollable release of therapeutic agents, result in reduced combined treatment efficacy. This study considered adenosine triphosphate (ATP), which is highly upregulated in tumor cells, as a biomarker and developed ingenious ATP-activated nanoparticles (CDNPs) that are directly self-assembled from near-infrared photosensitizer (Cy-I) and amphiphilic Cd(II) complex (DPA-Cd). After selective entry into tumor cells, the positively charged CDNPs would escape from lysosomes and be disintegrated by the high ATP concentration in the cytoplasm. The released Cy-I is capable of producing single oxygen (1 O2 ) for PDT with 808 nm irradiation and DPA-Cd can concurrently function for chemotherapy. Irradiation with 808 nm light can lead to tumor ablation in tumor-bearing mice after intravenous injection of CDNPs. This carrier-free nanoparticle offers a new platform for chemo-photodynamic therapy.

Development of Ruthenium Nanophotocages with Red or Near-Infrared Light-Responsiveness.

The development of light-triggered ruthenium (Ru) nanophotocages has revolutionized conventional methods of drug administration, thereby facilitating cancer therapy in a noninvasive and temperate manner. Ru nanophotocages employ a distinct approach known as photoactivated chemotherapy (PACT), wherein light-induced ligand dissociation yields a toxic metal complex or a ligand capable of performing other functions such as optically controlled protein degradation and drug delivery. Simultaneously, this process is accompanied by the generation of reactive oxygen species (ROS), which serve as an effective anticancer agent in combination with PACT and photodynamic therapy (PDT). Due to its exceptional attributes of extended tissue penetration, and minimized tissue damage, red light or near-infrared light is widely acknowledged as the "phototherapeutic window" (650-900 nm). In this Concept, we present an overview of the most recent advancements in Ru nanophotocages within the phototherapeutic range. Diverse aspects, including design principles, photocaging efficacy, photoactivation mechanisms, and potential applications in the field of biomedical chemistry, are discussed. Questions and challenges regarding their synthesis, characterization, and applications are also discussed. This Concept would foster further exploration into the realm of Ru nanophotocages.

Visible-Light-Promoted Mn-Catalyzed C(sp3)-H Amidation with Dioxazolones.

A visible-light-driven Mn-catalyzed C(sp3)-H amidation of diphenylmethane derivatives with dioxazolones was described. These reactions occur with an external photosensitizer-free process and feature satisfactory to good yields (up to 81%) under mild conditions. Mechanistic investigations revealed that the reaction proceeded via a Mn-acyl nitrene intermediate and that H-atom abstraction was the rate-determining step. Computational studies showed that the decarboxylation of dioxazolone depends on the conversion of ground sextet state dioxazolone-bounding Mn species to quartet spin state via visible-light irradiation.

State-of-the-art self-luminescence: a win-win situation.

Self-luminescence, which eliminates the real-time external optical excitation, can effectively avoid background autofluorescence in photoluminescence, endowing with ultrahigh signal-to-noise ratio and sensitivity in bioassay. Furthermore, in situ generated and emitted photons have been applied to develop excitation-free diagnostics and therapeutic agents against deeply seated diseases. "Enhanced" self-luminescence, referring to the aggregation-induced emission (AIE)-integrated self-luminescence systems, is endowed with not only the above merits but also other superiorities including stronger luminous brightness and longer half-life compared with "traditional" self-luminescence platforms. As an emerging and booming hotspot, the "enhanced" self-luminescence facilitated by the win-win cooperation of the aggregation-induced emission and self-luminescent techniques has become a powerful tool for interdisciplinary research. This tutorial review summarizes the advancements of AIE-assisted self-luminescence including chemiluminescence and afterglow imaging, starting from the discussion on the design and working principles, luminescent mechanisms of self-luminescence fuels, versatile integrated approaches and advantages, and a broad range of representative examples in biosensors and oncotherapy. Finally, the current challenges and perspectives are discussed to further actuate the development of "enhanced" self-luminescence agents for biomedical diagnosis and treatment.

A Near-Infrared Light-Activated Photocage Based on a Ruthenium Complex for Cancer Phototherapy.

Conventional photocages only respond to short wavelength light, which is a significant obstacle to developing efficient phototherapy in vivo. The development of photocages activated by near-infrared (NIR) light at wavelengths from 700 to 950 nm is important for in vivo studies but remains challenging. Herein, we describe the synthesis of a photocage based on a ruthenium (Ru) complex with NIR light-triggered photocleavage reaction. The commercial anticancer drug, tetrahydrocurcumin (THC), was coordinated to the RuII center to create the Ru-based photocage that is readily responsive to NIR light at 760 nm. The photocage inherited the anticancer properties of THC. As a proof-of-concept, we further engineered a self-assembled photocage-based nanoparticle system with amphiphilic block copolymers. Upon exposure to NIR light at 760 nm, the Ru complex-based photocages were released from the polymeric nanoparticles and efficiently inhibited tumor proliferation in vivo.

A Membrane Tension-Responsive Mechanosensitive DNA Nanomachine.

Membrane curvature reflects physical forces operating on the lipid membrane, which plays important roles in cellular processes. Here, we design a mechanosensitive DNA (MSD) nanomachine that mimics natural mechanosensitive PIEZO channels to convert the membrane tension changes of lipid vesicles with different sizes into fluorescence signals in real time. The MSD nanomachine consists of an archetypical six-helix-bundle DNA nanopore, cholesterol-based membrane anchors, and a solvatochromic fluorophore, spiropyran (SP). We find that the DNA nanopore effectively amplifies subtle variations of the membrane tension, which effectively induces the isomerization of weakly emissive SP into highly emissive merocyanine isomers for visualizing membrane tension changes. By measuring the membrane tension via the fluorescence of MSD nanomachine, we establish the correlation between the membrane tension and the curvature that follows the Young-Laplace equation. This DNA nanotechnology-enabled strategy opens new routes to studying membrane mechanics in physiological and pathological settings.

Liposomal Enzyme Nanoreactors Based on Nanoconfinement for Efficient Antitumor Therapy.

Enzymatic reactions can consume endogenous nutrients of tumors and produce cytotoxic species and are therefore promising tools for treating malignant tumors. Inspired by nature where enzymes are compartmentalized in membranes to achieve high reaction efficiency and separate biological processes with the environment, we develop liposomal nanoreactors that can perform enzymatic cascade reactions in the aqueous nanoconfinement of liposomes. The nanoreactors effectively inhibited tumor growth in vivo by consuming tumor nutrients (glucose and oxygen) and producing highly cytotoxic hydroxyl radicals (⋅OH). Co-compartmentalization of glucose oxidase (GOx) and horseradish peroxidase (HRP) in liposomes could increase local concentration of the intermediate product hydrogen peroxide (H2 O2 ) as well as the acidity due to the generation of gluconic acid by GOx. Both H2 O2 and acidity accelerate the second-step reaction by HRP, hence improving the overall efficiency of the cascade reaction. The biomimetic compartmentalization of enzymatic tandem reactions in biocompatible liposomes provides a promising direction for developing catalytic nanomedicines in antitumor therapy.

ER-Targeting Cyanine Dye as an NIR Photoinducer to Efficiently Trigger Photoimmunogenic Cancer Cell Death.

Endoplasmic reticulum (ER) stress, caused by overproduction of reactive oxygen species (ROS), has been shown to be responsible for immunogenic cell death (ICD). Seeking ROS generator targeting ER is an optimal solution to efficiently induce ER stress. Despite clear indications of demand for ER-targeting photosensitizer, the alternative chemical tools remain limited. Herein, the first ER-localizable ICD photoinducer using thio-pentamethine cyanine dye (TCy5) to induce ER stress under mild near-infrared (NIR) irradiation has been developed. Within the ICD photoinducer design, polyfluorinated TCy5-Ph-3F possesses a selective tropism to ER accumulation and superior ROS generation capability in both normoxia and hypoxia conditions, which benefit from its low singlet-triplet gaps. Under NIR irradiation, cancer cells stained by TCy5-Ph-3F will lead to ER stress and induce massive emission of damage-associated molecular patterns, including calreticulin and heat-shock protein 70 exposure, high mobility group box 1 efflux, and adenosine triphosphate secretion. Dendritic cells maturation and CD8+ T cells activation in vivo also highlight the effectiveness. Therefore, the growth of abscopal tumors was substantially suppressed by the primary tumor treated with TCy5-Ph-3F and NIR irradiation. These results confer practical applicability that could provide a guideline for designing efficient ICD photoinducers, which will enable expanding organic molecular applications for cancer immunotherapy.

Urea-Bond Scission Induced by Therapeutic Ultrasound for Biofunctional Molecule Release.

Ultrasound-triggered remote control of biomolecular functions in cells provides unique advantages for us to interrogate nature. However, strategies to design therapeutic ultrasound-responsive functional molecules remain elusive, and rare ultrasound-cleavable chemical bonds have been developed to date. Herein, therapeutic ultrasound (1 MHz)-induced scission of urea bonds for drug release is demonstrated for the first time. Such a transformation has been verified to be initiated by hydroxyl radicals generated in the interior of cavitation bubbles, occurring specifically at the cavitation bubble-liquid interface. A series of urea-bond-containing prodrugs based on methylene blue (MB), namely MBUs, are designed. Upon sonication with low-intensity therapeutic ultrasound, the urea bonds linked with primary amines can be selectively cleaved, and free MB is released in a physiologically relevant environment, accompanied by recovered absorbance, fluorescence, and photosensitivity. Moreover, an FDA-approved alkylating agent (i.e., melphalan) bearing urea bond is also developed (MBU-Mel), successfully achieving ultrasound-triggered drug release in deep-seated cancer cells (mimic with 1 cm pigskin), showing the scalability of our ultrasound-responsive molecule platform in bioactive molecules release. This may set the starting point for therapeutic ultrasound-induced drug release, making a forward step in "sonopharmacology".

Biodegradable Ru-Containing Polycarbonate Micelles for Photoinduced Anticancer Multitherapeutic Agent Delivery and Phototherapy Enhancement.

The lack of selectivity between tumor and healthy cells, along with inefficient reactive oxygen species production in solid tumors, are two major impediments to the development of anticancer Ru complexes. The development of photoinduced combination therapy based on biodegradable polymers that can be light activated in the "therapeutic window" would be beneficial for enhancing the therapeutic efficacy of Ru complexes. Herein, a biodegradable Ru-containing polymer (poly(DCARu)) is developed, in which two different therapeutics (the drug and the Ru complex) are rationally integrated and then conjugated to a diblock copolymer (MPEG-b-PMCC) containing hydrophilic poly(ethylene glycol) and cyano-functionalized polycarbonate with good degradability and biocompatibility. The polymer self-assembles into micelles with high drug loading capacity, which can be efficiently internalized into tumor cells. Red light induces the generation of singlet oxygen and the release of anticancer drug-Ru complex conjugates from poly(DCARu) micelles, hence inhibiting tumor cell growth. Furthermore, the phototherapy of polymer micelles demonstrates remarkable inhibition of tumor growth in vivo. Meanwhile, polymer micelles exhibit good biocompatibility with blood and healthy tissues, which opens up opportunities for multitherapeutic agent delivery and enhanced phototherapy.

Recent progress in photosensitizers for overcoming the challenges of photodynamic therapy: from molecular design to application.

Photodynamic therapy (PDT), a therapeutic mode involving light triggering, has been recognized as an attractive oncotherapy treatment. However, nonnegligible challenges remain for its further clinical use, including finite tumor suppression, poor tumor targeting, and limited therapeutic depth. The photosensitizer (PS), being the most important element of PDT, plays a decisive role in PDT treatment. This review summarizes recent progress made in the development of PSs for overcoming the above challenges. This progress has included PSs developed to display enhanced tolerance of the tumor microenvironment, improved tumor-specific selectivity, and feasibility of use in deep tissue. Based on their molecular photophysical properties and design directions, the PSs are classified by parent structures, which are discussed in detail from the molecular design to application. Finally, a brief summary of current strategies for designing PSs and future perspectives are also presented. We expect the information provided in this review to spur the further design of PSs and the clinical development of PDT-mediated cancer treatments.