Type-I photodynamic therapy (PDT) is highly effective against hypoxic tumors, with its efficacy further enhanced by near-infrared-II (NIR-II, 1000-1700 nm) excitation, which offers deeper tissue penetration than conventional NIR-I (700-1000 nm). However, most reported organic NIR-II photosensitizers (PSs) are only NIR-II emissive but remain NIR-I-excited. NIR-II-excited type-I PSs are rare and generally limited by low ROS yields, often requiring high-power irradiation with photothermal co-treatment to achieve meaningful therapeutic outcomes. Thus, rationally designing efficient organic type-I PSs directly activated by NIR-II light remains a challenge. Herein, we report a general strategy for designing efficient NIR-II-excited organic Type-I PSs (PNT-PFT NPs) based on linked donor-acceptor through-space charge transfer (CT) for PDT of hypoxic solid tumors. The through-space CT based on linked donor-acceptor pairs redshifts and amplifies the NIR-II absorption of the PNT-PFT NPs. Additionally, the donor-acceptor energy alignment facilitates directional flow of electrons, increasing free-electron yield for O2-to-ROS conversion. As a result, PNT-PFT NPs efficiently generated ROS and achieved 89.3% tumor inhibition in 4T1 models under low-power 1064nm irradiation. This study not only offers a general guideline for tailoring NIR-II-excited Type-I PSs via through-space CT in linked donor-acceptor pairs but also provides mechanistic insights into Type-I PS design.

Natural Chlorin e ₆ Derivative Containing a Cationic Dimethyl Piperazinyl Moiety for Efficient Photodynamic Therapy of Cancer

Manganese dioxide (MnO2) nanoparticles have been reported to deliver drugs, supply oxygen and consume glutathione (GSH) to promote cancer photodynamic therapy (PDT). However, most of them suffer from low drug loading capacity and conflicting oxygen/GSH tuning, which restricts their therapeutic potential. In this study, a high capacity MnO2-derived multifunctional nanocarrier was designed to alleviate tumor hypoxia, one of the most critical conditions for effective PDT, by systematically modulating local oxygen supply and GSH depletion. The prepared MnO2 (MH) nanoaggregates were coated with catalase (CAT) through molecular assembly and chemical crosslinking, yielding the MH@CAT nanocomposite. In the presence of hydrogen peroxide (H2O2), the CAT coating facilitates oxygen generation, while the MnO2 core remains intact until encountering intracellular GSH, resulting in MnO2 decomposition and GSH draining. This programmed regulation of oxygen supply and GSH consumption is a key design to optimize the tumor microenvironment for enhanced PDT. After loading chlorin e6 (Ce6), the as-prepared MH@CAT-Ce6 demonstrates improved cellular uptake, oxygen self-supply, and GSH depletion - all of which contribute to the superior PDT effects observed against breast cancer cells both in vitro and in vivo. Notably, the MH@CAT-Ce6 nanoparticles exhibit excellent tumor accumulation and retention, leading to potent anti-tumor efficacy with minimal systemic toxicity.

Engineering tactics for organelle targeting behavior and PDT efficiency by fine structural regulation.

This study develops Ni-doped carbon dots (Ni-CDs) that mediate synergistic photothermal and photodynamic dual-modal tumor therapy under single 1064 nm NIR-II laser excitation, and are successfully applied to tumor treatment in mice.

Black phosphorus-based drug nanocarrier for synergetic chemo-, chemo-dynamic, and photo-dynamic therapy of liver cancer.

Halogen substituted 4-thio-2'-deoxyuridines as photosensitizers for the photodynamic therapy of prostate cancer. An in vitro study.

A multifunctional M1-like cell vehicle to intravesically deliver ICG for photodynamic therapy of bladder cancer.

Enhancing intratumoral spread of radioluminescent nanoparticles via collagenase functionalization for radiation-induced photodynamic cancer therapy.

ConspectusCancer remains a leading cause of death worldwide. Phototheranostic tools, known for their rapid response and high precision, have opened new avenues for cancer diagnosis and treatment. As a pioneering agent, Nile Blue (NB) dye has attracted significant interest due to its excellent chemical stability, lipophilicity, and near-infrared (NIR) excitation/emission properties, establishing itself as a reference molecular platform in biomedicine.Our research journey with NB began with its remarkable potential as a fluorescence probe in the field of bioimaging for disease diagnosis. As research progressed, we began to explore structural modifications to expand its functional boundaries. A key breakthrough from our team in 2018 revealed that replacing the central oxygen (O) atom in the NB structure with a sulfur (S) atom significantly enhanced the intersystem crossing (ISC) rate of the resulting analog ENBS, enabling its use as a specific superoxide anion (O2•-) photosensitizer (PS) for low O2-dependent photodynamic therapy (PDT) (J. Am. Chem. Soc. 2018, 140, 14851-14859).This discovery opened the door to optimizing ENBS via "chalcogen atomic engineering" and inspired our intensive research into systematic modifications of the NB framework, such as by conjugating drug molecules, targeting groups and activation sites. We contributed a series of ENBS derivatives widely used in cancer PDT. Another representative study involved replacing the central O in NB with a selenium (Se) atom. The resulting compound, ENBSe, capable of functioning as a photocatalyst (PC), exhibited a significantly improved triplet state efficiency (J. Am. Chem. Soc. 2022, 144, 163-173). By triggering cellular biomolecular conversion (e.g., nicotinamide adenine dinucleotide (NADH) oxidation and cytochrome c (Cyt c (Fe3+)) reduction) and interfering with the mitochondrial respiratory chain, ENBSe effectively addressed certain challenges in biocatalysis. Importantly, the entire process is O2-independent, offering a new strategy for treating hypoxic tumors. These systematic and in-depth research efforts have earned our research group a distinctive "Nile Blue" label in the field, resulting in a plethora of NB analogs developed by many groups around the world.During the past 10 years, our research group has employed a "chalcogen atom substitution" strategy to systematically develop O/S/Se-modified NB derivatives, making significant contributions to the design of phototheranostic tools. Throughout this evolutionary process, NB has progressed from a simple fluorescent bioimaging probe to an innovative therapeutic agent and ultimately into a groundbreaking biophotoredox catalyst. In this comprehensive Account, we begin with a brief historical overview of NB dyes, then trace the developmental trajectory of NB, ENBS, and ENBSe to thoroughly present the innovative achievements. Finally, we conclude with a critical perspective on the clinical translation potential of NB-based analogs. We are convinced that our summarized work of the "single molecular scaffold, multiple theranostic functions" paradigm will redefine the development of next-generation phototheranostic agents, driving transformative advances in healthcare.

A novel metal-organic coordination polymer based on Ru complexes for photoredox catalysis and photodynamic therapy of breast cancer

Pancreatic cancers often involve major blood vessels, making complete surgical removal difficult or impossible. We are developing endovascular photodynamic therapy (PDT) as a novel minimally invasive ablation method to clear tumours from these vessels, to enable potentially curative surgery. The goal is to determine the required endovascular irradiation times for effective treatment. Threshold doses for PDT were estimated using Monte Carlo simulations, based on clinical data from previous Phase I/II studies involving Photodynamic Therapy of pancreatic cancer using interstitial needle-based irradiation. These thresholds were then compared to our recent in vivo study, which used endovascular catheter-based irradiation in a normal pig pancreas. Using these dose thresholds, we estimated the PDT irradiation times needed to achieve necrotic tissue margins of 4-12mm around blood vessels in pancreatic cancer patients, based on a fixed energy range and increasing doses of photosensitiser. The threshold dose for Verteporfin-mediated PDT was determined to be 1.43-2.37 × 1017 hvcm⁻3 for human pancreatic cancer and 1.27 × 1018 hvcm⁻3 for normal pig pancreas. Based on these values, and assuming homogeneous tissue optical properties and a Verteporfin dose of 0.4mgkg⁻1, and an optical power of 300 mWcm-2 @ 690nm, necrotic margins of circa 8mm beyond the vessel adventitia can be anticipated in pancreatic cancer patients. The required irradiation times range from 337 to 636s, inversely related to vessel diameters of 10mm and 3mm, respectively. These findings suggest that PDT can potentially create a margin around major pancreatic blood vessels free of viable tumour tissue. The calculated dosimetry supports the feasibility of clinical application using the proposed Verteporfin dose and light delivery parameters, warranting further investigation in Clinical trials.

Enhanced in vitro photodynamic therapy for triple-negative breast cancer by pheophorbide a-encapsulated chitosan-tripolyphosphate nanoparticles.

.SignificancePhotodynamic therapy (PDT) for the treatment of oral cancers and oral potentially malignant lesions can be enhanced by the capability of the photosensitizer to serve as a fluorescence contrast agent for treatment guidance. The development of image-based dosimetry reporters can inform treatment progress in real time to avoid under-treatment, leading to incomplete response and recurrence.AimWe investigate the hypothesis that imaging of protoporphyrin IX (PpIX) photoproduct (PP) accumulation may be leveraged as an implicit PDT dosimetry reporter for PDT using 5-aminolevulinic acid (ALA)-induced PpIX photosensitization.ApproachIn initial spectroscopy studies, we investigate dose-dependent changes in absorption and fluorescence spectra of PpIX corresponding to PP accumulation during red light (635 nm) delivery. We use spectral analysis to select fluorescence excitation and spectral filtering components for PP imaging during treatment. We evaluate the capability for imaging PP accumulation concomitant with PpIX photobleaching in tissue phantoms, 3D oral squamous cell carcinoma (OSCC) models, and in murine xenografts.ResultsSpectroscopy shows fluence-dependent changes in PpIX optical properties, and that excitation of photobleached PpIX with 450 nm light produces fluorescence emission associated with PpIX PPs. An existing handheld intraoral probe is shown to be capable of imaging dose-dependent PP accumulation with the addition of a spectral filter to isolate fluorescence emission longer than 650 nm. PP signal increases concomitant with PpIX photobleaching in a fluence-dependent manner and correlates with the extent of cytotoxic response in 3D cultures. PP accumulation is also observed to occur concomitantly with photobleaching in OSCC subcutaneous xenografts.ConclusionsOverall, the results show that imaging of PP accumulation is feasible by adapting traditional photodiagnosis optical components and may serve as a dosimetry reporter for ALA-PDT, which is complementary to the measurement of PpIX photobleaching.

Self-healing chitosan/starch hydrogel as carrier of photosensitizers based on polythiophene/boron nitride nanotubes for photodynamic therapy of cancer cells.

Nano-enhanced photodynamic therapy and machine learning: Advancements, challenges, and future directions.

This study investigates the enhancement of photodynamic therapy (PDT) efficacy through the encapsulation of platinum phthalocyanine (Pc) in albumin nanoparticles (ANP). Encapsulation of Pc in ANP) significantly enhances its biological effects in photodynamic therapy by increasing cellular uptake through receptor-mediated endocytosis and promoting lysosomal accumulation. This leads to marked lysosomal stress and regulated necrotic cell death pathway, while free Pc causes moderate oxidative stress with reversible apoptosis and autophagy. The enhanced phototoxicity of encapsulated Pc was evident across multiple cancer cell lines, especially aggressive phenotypes, whereas resistant lines showed lower sensitivity likely due to efficient ROS scavenging. Despite improved initial uptake, rapid lysosomal release and extracellular extrusion of Pc limit long-term intracellular retention. Morphological and gene expression analyses confirmed distinct cell death mechanisms between free and encapsulated Pc, underscoring the critical role of nanocarrier-mediated delivery in modulating oxidative stress and cellular response. These findings highlight the importance of nanoparticle design in optimizing PDT efficacy by effectively triggering necrotic cell death pathway.

Photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment due to high spatiotemporal selectivity. However, most of the conventional photosensitizers (as the core component of PDT) are activated by visible light, which suffers from limited tissue penetration, thereby restricting the clinical applications of PDT. In this study, two carboxymethyl-functionalized aggregation-induced emission (AIE) compounds, (E)-2-(4-(bis(4-methoxyphenyl)amino)styryl)-5-carboxy-3-methylbenzo[d]thiazol-3-ium (MOTBAC) and (E)-5-carboxy-2-(2-(5-(4-(diphenylamino)phenyl)thiophen-2-yl)vinyl)-3-methylbenzo[d]thiazol-3-ium (TTBAC), were synthesized and coordinated with upconversion nanoparticles (UCNPs) to form UCNPs-MOTBAC and UCNPs-TTBAC nanoconjugates, which generate reactive oxygen species (ROS) under 980-nm irradiation. The energy transfer efficiencies from UCNPs to MOTBAC and TTBAC were 29.4% and 33.9%, respectively. To enhance TTBAC loading, TTBAC was silanized and covalently grafted onto the UCNPs@mSiO2, while free TTBAC molecules were incorporated into the porous silica network. The resulting nanoparticles were further modified with DSPE-PEG2000 to obtain USiTT. Compared with UCNPs-TTBAC nanoconjugates, the USiTT nanoparticles exhibited increased TTBAC loading (5.08% vs. 4.20%), higher encapsulation efficiency (95.88% vs. 79.30%), and enhanced energy transfer efficiency (38.78%). Cellular uptake experiments revealed that USiTT primarily accumulated at lysosomes. Phototoxicity assays and live/dead cell staining experiments demonstrated that the UCNPs in USiTT could activate TTBAC and generate ROS, resulting in cancer cell ablation. The method of constructing USiTT nanoparticles could effectively enhance the loading capacity of photosensitizers and improve energy transfer of UCNPs, ensuring that ROS could be effectively generated under NIR irradiation. Furthermore, the nanomaterials can target the lysosome, which offered a potential strategy for the development of NIR-activated nanomaterials in precision photodynamic therapy.

Squaraine dyes are a class of organic compounds that exhibit some characteristics inherent to those of an "ideal photosensitizer", such as high absorption at near-infrared-close wavelengths and to produce reactive oxygen species. The introduction of amines into their squaric ring, although known to increase the phototoxicity of squaraines, can improve dyes' water solubility and induce bathochromic shifts compared to their unsubstituted derivatives, interesting effects in biological contexts. In this work, four new squaraines were synthesized and structurally, photophysically, and photochemically characterized (including absorption and aggregation, fluorescence, light stability, and singlet oxygen generation). Their potential as fluorescent probes for albumin detection was assessed through both in silico and in vitro approaches, as well as their suitability as potential photosensitizers for photodynamic therapy. For this last purpose, the 663 nm light-induced effects of the new dyes were evaluated against the PC-3 prostate cancer cell line, while their photocytotoxicity toward normal human dermal fibroblasts was also assessed using the MTT assay, to determine their potential tumor-selective effects. Low singlet oxygen quantum yields suggest that type I reactions predominate in generating cytotoxicity. Overall, the findings indicate that the designed squaraines exhibit moderate yet favorable interactions with albumin protein while demonstrating selective photodynamic effects toward prostate adenocarcinoma cancer cells, highlighting their potential as protein-assisted, tumor-targeted photosensitizers, providing a basis for further mechanistic studies.

Ferroptosis, a regulated form of non-apoptotic cell death driven by iron-dependent lipid peroxidation, has emerged as a promising approach for overcoming therapy-resistant cancers. A multifunctional lipid nanoparticle (LNP) platform was developed to integrate ferroptosis induction with photodynamic therapy (PDT) for synergistic anticancer effects. By partially substituting cholesterol in conventional DLin-MC3-DMA (MC3)-based LNPs with cholesterol-polyethylene glycol (PEG)-pheophorbide a (CPP), we engineered photosensitizing lipid nanoparticles (PLNPs) capable of delivering glutathione peroxidase 4 (GPX4)-targeting small interfering RNA (siRNA). Upon laser irradiation, the PLNPs generate reactive oxygen species (ROS) through PDT, while siRNA-mediated GPX4 silencing promotes ferroptosis by disrupting cellular antioxidant defenses. The PLNPs demonstrate favorable physicochemical characteristics, efficient gene silencing, and potent ROS production. In vitro experiments in 4T1 and EO771 breast cancer cells reveal enhanced cytotoxicity under combined treatment, underscoring the synergistic interaction between PDT-induced oxidative stress and ferroptotic cell death. In vivo, the PLNPs exhibit prolonged tumor retention, effective GPX4 knockdown, and significant tumor growth inhibition, with minimal systemic toxicity. Overall, this work introduces a dual-function nanoplatform that potentiates photodynamic cancer therapy through ferroptosis induction and offers a versatile strategy for developing next-generation combination treatments targeting aggressive tumors.