Mitochondria-targeted BODIPY dyes for small molecule recognition, bio-imaging and photodynamic therapy.

Mitochondria are essential for a diverse array of biological functions. There is increasing research focus on developing efficient tools for mitochondria-targeted detection and treatment. BODIPY dyes, known for their structural versatility and excellent spectroscopic properties, are being actively explored in this context. Numerous studies have focused on developing innovative BODIPYs that utilize optical signals for imaging mitochondria. This review presents a comprehensive overview of the progress made in this field, aiming to investigate mitochondria-related biological events. It covers key factors such as design strategies, spectroscopic properties, and cytotoxicity, as well as mechanism to facilitate their future application in organelle imaging and targeted therapy. This work is anticipated to provide valuable insights for guiding future development and facilitating further investigation into mitochondria-related biological sensing and phototherapy.

BODIPY-Based Analogue of the TREM2-Binding Molecular Adjuvant Sulfavant A, a Chemical Tool for Imaging and Tracking Biological Systems.

Recently, we described synthetic sulfolipids named Sulfavants as a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton. The members of this family, Sulfavant A (1), Sulfavant R (2), and Sulfavant S (3), showed important effects on triggering receptor expressed on myeloid cells 2 (TREM2)-induced differentiation and maturation of human dendritic cells (hDC), through a novel cell mechanism underlying the regulation of the immune response. As these molecules are involved in biological TREM2-mediated processes crucial for cell survival, here, we report the synthesis and application of a fluorescent analogue of Sulfavant A bearing the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene moiety (Me4-BODIPY). The fluorescent derivative, named PB-SULF A (4), preserving the biological activity of Sulfavants, opens the way to chemical biology and cell biology experiments to better understand the interactions with cellular and in vivo organ targets and to improve our comprehension of complex molecular mechanisms underlying the not fully understood ligand-induced TREM2 activity.

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

Synthesis and Photophysical Study of Tetraphenyl Substituted BODIPY Based Phenyl-Monoselenide Probe for Selective Detection of Superoxide.

Selenium containing tetraphenyl substituted BODIPY probe was successfully synthesized from respective selenium aldehyde and tetraphenyl pyrrole using Knoevenagel-type condensation. The product was characterized using various spectroscopic techniques (1 H, 13 C, 77Se, 11B, and 19 F) and mass spectrometry. The probe was found to be selective and sensitive towards detection of superoxide over other ROS with a "turn-off" (quenched) fluorescence response. The detection limit of the probe was found to be 4.87 µM. The probe reacted with superoxide in less than a sec with a stoke shift of 35 nm.

Synthesis of aza-BODIPYs with barrier-free rotation of the -tBu group at 3-site and enhancement of photothermal therapy by triggering cancer cell apoptosis.

Breaking through the traditional 1,7,3,5-aryl substituted aza-BODIPY structure, asymmetric aza-BODIPYs, tBu-azaBDPs, containing non-aryl group at 3-site were prepared for the first time. tBu-azaBDP exhibited a severely twisted configuration. tBu-azaBDPs had a near-infrared fluorescence emission and high molar extinction coefficients. Although the barrier-free rotation of the distal -tBu group in tBu-azaBDP resulted in low fluorescence quantum yield, the photothermal conversion efficiency was markedly enhanced. tBu-azaBDP nanoparticles with laser irradiation were revealed to induce cell apoptosis in photothermal therapy. We consider that development of aza-BODIPYs with the barrier-free rotation of the -tBu group at 3-site provides a strong platform for design of phototherapy agents for cancer treatment in photothermal therapy by apoptosis.

A Comparison of the Photophysical, Electrochemical and Cytotoxic Properties of meso-(2-, 3- and 4-Pyridyl)-BODIPYs and Their Derivatives.

Boron dipyrromethene (BODIPY) dyes bearing a pyridyl moiety have been used as metal ion sensors, pH sensors, fluorescence probes, and as sensitizers for phototherapy. A comparative study of the properties of the three structural isomers of meso-pyridyl-BODIPYs, their 2,6-dichloro derivatives, and their corresponding methylated cationic pyridinium-BODIPYs was conducted using spectroscopic and electrochemical methods, X-ray analyses, and TD-DFT calculations. Among the neutral derivatives, the 3Py and 4Py isomers showed the highest relative fluorescence quantum yields in organic solvents, which were further enhanced 2-4-fold via the introduction of two chlorines at the 2,6-positions. Among the cationic derivatives, the 2catPy showed the highest relative fluorescence quantum yield in organic solvents, which was further enhanced by the use of a bulky counter anion (PF6-). In water, the quantum yields were greatly reduced for all three isomers but were shown to be enhanced upon introduction of 2,6-dichloro groups. Our results indicate that 2,6-dichloro-meso-(2- and 3-pyridinium)-BODIPYs are the most promising for sensing applications. Furthermore, all pyridinium BODIPYs are highly water-soluble and display low cytotoxicity towards human HEp2 cells.

Aggregation behavior and spectroscopic properties of red-emitting distyryl-BODIPY in aqueous solution, Langmuir-Schaefer films and Pluoronic® F127 micelles.

Red-emitting distyryl substituted BODIPY dyes are among the most promising luminophors for bioimaging and optics applications. However, the practical application of BODIPYs is limited due to their high hydrophobicity and tendency to aggregate in aqueous organic solutions and solid phase. In this article, we propose an elegant solution to this problem. To this end, we carried out the detailed experimental and quantum-chemical study of the structural and spectral features of BF2-ms-phenyl-5,5'-bis(4-dimethylaminostyryl)-3,3'-dimethyl-2,2'-dipyrromethene (distyryl-BDP). The particular attention was paid to analysis of high sensitivity of the distyryl-BDP spectral characteristics to the solvent properties, and also the aggregation behavior features both in water-organic media and in mono- and multilayer Langmuir-Schaefer films. We selected the best conditions to obtain the hydrophilic micellar structures of distyryl-BDP with Pluronic® F127 having a high efficiency of dye solubilization. This method increasing the solubility improves the distyryl-BDP transport efficiency in physiological aqueous media. The aqueous solutions of distyryl-BDP-Pl micelles show the intense fluorescence in the phototherapy window region (λfl = 739 nm).

Discovery of Meso-(meta-Pyridinium) BODIPY Photosensitizers: In Vitro and In Vivo Evaluations for Antimicrobial Photodynamic Therapy.

Antimicrobial photodynamic therapy (aPDT) has emerged as a novel and promising approach for the treatment of pathogenic microorganism infections. The efficacy of aPDT depends greatly on the behavior of the photosensitizer. Herein, we report the design, preparation, antimicrobial photodynamic activities, as well as structure-activity relationships of a series of photosensitizers modified at the meso position of a 1,3,5,7-tetramethyl BODIPY scaffold with various pyridinyl and pyridinium moieties. The photodynamic antimicrobial activities of all photosensitizers have been tested against Staphylococcus aureus, Escherichia coli, Candida albicans, and Methicillin-resistant S. aureus (MRSA). The methyl meso-(meta-pyridinium) BODIPY photosensitizer (3c) possessed the highest phototoxicity against these pathogens at minimal inhibitory concentrations (MIC) ranging from 0.63 to 1.25 µM with a light dose of 81 J/cm2. Furthermore, 3c exhibited an impressive antimicrobial efficacy in S. aureus-infected mice wounds. Taken together, these findings suggest that 3c is a promising candidate as the antimicrobial photosensitizer for combating pathogenic microorganism infections.

Homocystamide Conjugates of Human Serum Albumin as a Platform to Prepare Bimodal Multidrug Delivery Systems for Boron Neutron Capture Therapy.

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)-a carrier protein with a long plasma half-life-is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-'click' chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro-closo-dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 µM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro-closo-dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

Leveraging BODIPY nanomaterials for enhanced tumor photothermal therapy.

In the past ten years, photothermal therapy (PTT) has attracted widespread attention in tumor treatment due to its non-invasiveness and little side effects. PTT utilizes heat produced by photothermal agents under the irradiation of near-infrared light to kill tumor cells. Boron-dipyrromethene (BODIPY), an organic phototherapy agent, has been widely used in tumor phototherapy due to its higher molar extinction coefficient, robust photostability and good phototherapy effect. However, there are some issues in the application of BODIPY for tumor PTT, such as low photothermal conversion efficiency and short absorption wavelength. In this review, we focus on the latest development of BODIPY nanomaterials for overcoming the above problems and enhancing the PTT effect.

Highly Efficient Far-Red/NIR-Absorbing Neutral Ir(III) Complex Micelles for Potent Photodynamic/Photothermal Therapy.

A critical issue in photodynamic therapy (PDT) is inadequate reactive oxygen species (ROS) generation in tumors, causing inevitable survival of tumor cells that usually results in tumor recurrence and metastasis. Existing photosensitizers frequently suffer from relatively low light-to-ROS conversion efficiency with far-red/near-infrared (NIR) light excitation due to low-lying excited states that lead to rapid non-radiative decays. Here, a neutral Ir(III) complex bearing distyryl boron dipyrromethene (BODIPY-Ir) is reported to efficiently produce both ROS and hyperthermia upon far-red light activation for potentiating in vivo tumor suppression through micellization of BODIPY-Ir to form "Micelle-Ir". BODIPY-Ir absorbs strongly at 550-750 nm with a band maximum at 685 nm, and possesses a long-lived triplet excited state with sufficient non-radiative decays. Upon micellization, BODIPY-Ir forms J-type aggregates within Micelle-Ir, which boosts both singlet oxygen generation and the photothermal effect through the high molar extinction coefficient and amplification of light-to-ROS/heat conversion, causing severe cell apoptosis. Bifunctional Micelle-Ir that accumulates in tumors completely destroys orthotopic 4T1 breast tumors via synergistic PDT/photothermal therapy (PTT) damage under light irradiation, and enables remarkable suppression of metastatic nodules in the lungs, together without significant dark cytotoxicity. The present study offers an emerging approach to develop far-red/NIR photosensitizers toward potent cancer therapy.

Borosilicate glass 60Co high dose rate brachytherapy thermoluminescence dosimetry.

Brachytherapy is commonly used in treatment of cervical, prostate, breast and skin cancers, also for oral cancers, typically via the application of sealed radioactive sources that are inserted within or alongside the area to be treated. A particular aim of the various brachytherapy techniques is to accurately transfer to the targeted tumour the largest possible dose, at the same time minimizing dose to the surrounding normal tissue, including organs at risk. The dose fall-off with distance from the sources is steep, the dose gradient representing a prime factor in determining the dose distribution, also representing a challenge to the conduct of measurements around sources. Amorphous borosilicate glass (B2O3) in the form of microscope cover slips is recognized to offer a practicable system for such thermoluminescence dosimetry (TLD), providing for high-spatial resolution (down to < 1 mm), wide dynamic dose range, good reproducibility and reusability, minimal fading, resistance to water and low cost. Herein, investigation is made of the proposed dosimeter using a 1.25 MeV High Dose Rate (HDR) 60Co brachytherapy source, characterizing dose response, sensitivity, linearity index and fading. Analysis of the TL glow curves were obtained using the Tmax-Tstop method and first-order kinetics using GlowFit software, detailing the frequency factors and activation energy.

Twisted BODIPY derivative: intersystem crossing, electron spin polarization and application as a novel photodynamic therapy reagent.

The photophysical properties of a heavy atom-free BODIPY derivative with a twisted π-conjugated framework were studied. Efficient intersystem crossing (ISC quantum yield: 56%) and an exceptionally long-lived triplet state were observed (4.5 ms in solid polymer film matrix and 197.5 µs in solution). Time-resolved electron paramagnetic resonance (TREPR) spectroscopy and DFT computations confirmed the delocalization of the triplet state on the whole twisted π-conjugated framework and the zero-field-splitting (ZFS) D parameter of D = -69.5 mT, which is smaller than that of 2,6-diiodoBODIPY (D = -104.6 mT). The electron spin polarization (ESP) phase pattern of the triplet state TREPR spectrum of the twisted BODIPY is (a, a, e, a, e, e), which is different from that of 2,6-diiodo BODIPY (e, e, e, a, a, a), indicating that the electron spin selectivity of the ISC of the twisted structure is different from that of the spin orbital coupling effect. According to the computed spin-orbit coupling matrix elements (0.154-1.964 cm-1), together with the matched energy of the S1/Tn states, ISC was proposed to occur via S1→T2/T3. The computational results were consistent with TREPR results on the electron spin selectivity (the overpopulation of the TY sublevel of the T1 state). The advantage of the long-lived triplet state of the twisted BODIPY was demonstrated by its efficient singlet oxygen (1O2) photosensitizing (ΦΔ = 50.0%) even under a severe hypoxia atmosphere (pO2 = 0.2%, v/v). A high light toxicity (EC50 = 1.0 µM) and low dark toxicity (EC50 = 78.5 µM) were observed for the twisted BODIPY, and thus the cellular studies demonstrate its potential as a novel potent heavy atom-free photodynamic therapy (PDT) agent.

A Cysteine-Mediated Synthesis of Red Phosphorus Nanosheets.

Among phosphorus-based nanomaterials, layered black phosphorus and violet phosphorus have been actively explored in the past decade. However, methods for the synthesis of red phosphorus nanosheets (RPNSs) is lacking, even though red phosphorus (RP) is commercially available at low cost and has excellent chemical stability at room temperature. We report an efficient strategy for fabrication of RPNSs and doped RPNSs using cysteine as a reducing reagent. Data from in vitro and in vivo studies suggested that RPNSs can trigger production of reactive oxygen species, DNA damage, and subsequent autophagy-mediated cell death in a shape-dependent manner. Our findings provide a method for construction of layered RP nanomaterials and they present a unique mechanism for the application of phosphorus-based materials in nanomedicines.

Polystyrene Microparticles with Convergently Grown Mesoporous Silica Shells as a Promising Tool for Multiplexed Bioanalytical Assays.

Functional core/shell particles are highly sought after in analytical chemistry, especially in methods suitable for single-particle analysis such as flow cytometry because they allow for facile multiplexed detection of several analytes in a single run. Aiming to develop a powerful bead platform of which the core particle can be doped in a straightforward manner while the shell offers the highest possible sensitivity when functionalized with (bio)chemical binders, polystyrene particles were coated with different kinds of mesoporous silica shells in a convergent growth approach. Mesoporous shells allow us to obtain distinctly higher surface areas in comparison with conventional nonporous shells. While assessing the potential of narrow- as well as wide-pore silicas such as Mobil composition of matter no. 41 (MCM-41) and Santa Barbara amorphous material no. 15 (SBA-15), especially the synthesis of the latter shells that are much more suitable for biomolecule anchoring was optimized by altering the pH and both, the amount and type of the mediator salt. Our studies showed that the best performing material resulted from a synthesis using neutral conditions and MgSO4 as an ionic mediator. The analytical potential of the particles was investigated in flow cytometric DNA assays after their respective functionalization for individual and multiplexed detection of short oligonucleotide strands. These experiments revealed that a two-step modification of the silica surface with amino silane and succinic anhydride prior to coupling of an amino-terminated capture DNA (c-DNA) strand is superior to coupling carboxylic acid-terminated c-DNA to aminated core/shell particles, yielding limits of detection (LOD) down to 5 pM for a hybridization assay, using labeled complementary single-stranded target DNA (t-DNA) 15mers. The potential of the use of the particles in multiplexed analysis was shown with the aid of dye-doped core particles carrying a respective SBA-15 shell. Characteristic genomic sequences of human papillomaviruses (HPV) were chosen as the t-DNA analytes here, since their high relevance as carcinogens and the high number of different pathogens is a relevant model case. The title particles showed a promising performance and allowed us to unequivocally detect the different high- and low-risk HPV types in a single experimental run.

Manipulating the Dynamics of Dark Excited States in Organic Materials for Phototheranostics.

Manipulating the dynamics of dark excited states (DESs), such as higher excited singlet or excited triplet states with no or small radiative decay, are of both fundamental and practical interests, an important application being photoactivated diagnosis and therapy (phototheranostics), which include photoacoustic (PA) imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). However, the current understanding of DESs in organic structures is rather limited, thus making any rational manipulation of DES in organic materials very challenging.A DES decays primarily by radiationless transition through two pathways: (i) singlet-to-triplet intersystem crossing (ISC) and (ii) internal conversion (IC) relaxation. The deactivation of a DES via ISC can generate cytotoxic reactive oxygen species (ROS) for PDT, while IC could convert photons into heat for PA imaging and PTT. In this Account, we highlight our research on developing a fundamental understanding of structure-property relationships for manipulation of DESs in organic materials in relation to phototheranostic applications. We describe the application of femtosecond transient absorption (fs-TA) spectroscopy for obtaining valuable insights into the DES dynamics. Afterward, we present our work on DESs in nonrigid molecules that revealed greatly enhanced ISC through geometry twisting, which leads to an innovative pathway to develop organic materials exhibiting external stimuli-responsive reversible switching of ISC. We introduce the concept of smart PDT where highly efficient ISC imparted by geometry twisting in the acidic environment specific to tumors leads to very efficient and highly localized PDT, thus leaving surrounding healthy tissues at a different pH unaffected. This insightful understanding of ISC can lead to the development of more advanced photosensitizers for PDT. Two other emergent concepts from our work presented here are (1) significantly enhanced IC producing strong local heating by combining two-photon absorption with excited state absorption for cumulative multiphoton absorption, thus greatly increasing the strength of the PA signal for nonlinear PA imaging, and (2) shown by an example of an organic molecule, BODIPY, nanoscale charge-transfer state mediated strong IC in aggregate nanoparticles resulting in exceptionally high photothermal conversion efficiency of 61% for both PA and PTT. Some in vivo results of the phototheranostic studies using BODIPY are presented, providing an elegant example of nanoscale manipulation of the excited state dynamics.This Account concludes with a summary and discussion of future perspectives. We hope this Account will deepen the understanding of molecular and nanoscale control of excited state dynamics in organic materials, hopefully enticing a broad range of scientists within different disciplinary areas.

Terminal Mono- and Bis-Conjugates of Oligonucleotides with Closo-Dodecaborate: Synthesis and Physico-Chemical Properties.

Oligonucleotide conjugates with boron clusters have found applications in different fields of molecular biology, biotechnology, and biomedicine as potential agents for boron neutron capture therapy, siRNA components, and antisense agents. Particularly, the closo-dodecaborate anion represents a high-boron-containing residue with remarkable chemical stability and low toxicity, and is suitable for the engineering of different constructs for biomedicine and molecular biology. In the present work, we synthesized novel oligonucleotide conjugates of closo-dodecaborate attached to the 5'-, 3'-, or both terminal positions of DNA, RNA, 2'-O-Me RNA, and 2'-F-Py RNA oligomers. For their synthesis, we employed click reaction with the azido derivative of closo-dodecaborate. The key physicochemical characteristics of the conjugates have been investigated using high-performance liquid chromatography, gel electrophoresis, UV thermal melting, and circular dichroism spectroscopy. Incorporation of closo-dodecaborate residues at the 3'-end of all oligomers stabilized their complementary complexes, whereas analogous 5'-modification decreased duplex stability. Two boron clusters attached to the opposite ends of the oligomer only slightly influence the stability of complementary complexes of RNA oligonucleotide and its 2'-O-methyl and 2'-fluoro analogs. On the contrary, the same modification of DNA oligonucleotides significantly destabilized the DNA/DNA duplex but gave a strong stabilization of the duplex with an RNA target. According to circular dichroism spectroscopy results, two terminal closo-dodecaborate residues cause a prominent structural rearrangement of complementary complexes with a substantial shift from the B-form to the A-form of the double helix. The revealed changes of key characteristics of oligonucleotides caused by incorporation of terminal boron clusters, such as the increase of hydrophobicity, change of duplex stability, and prominent structural changes for DNA conjugates, should be taken into account for the development of antisense oligonucleotides, siRNAs, or aptamers bearing boron clusters. These features may also be used for engineering of developing NA constructs with pre-defined properties.

Bioapplications of small molecule Aza-BODIPY: from rational structural design to in vivo investigations.

Boron-dipyrromethene (BODIPY) belongs to a family of organoboron compounds, commercialized as fluorescent dyes by Invitrogen™. As BODIPY derivatives, Aza-boron-dipyrromethene (Aza-BODIPY) dyes display superior spectral performances, such as red-shifted spectra and high molar extinction coefficients, and are considered to be extremely attractive organic materials for various bioapplications. Therefore, scientists from different disciplinary backgrounds would benefit from a review that provides a timely summary and outlook regarding Aza-BODIPY dyes. In this review, we report on the latest advances of Aza-BODIPY dyes, along with the empirical design guidelines and photophysical property manipulation of these dyes. In addition, we will discuss the biological applications of Aza-BODIPY dyes in probing various biological activities, as well as in fluorescence bioimaging/detection, newly-emerging photoacoustic bioimaging/detection, and phototherapy together with future challenges and implications in this field. We aim at providing an insightful design guideline and a clear overview of Aza-BODIPY dyes, which might entice new ideas and directions.

Synthesis of enriched boron nitride nanocrystals: A potential element for biomedical applications.

The shortcomings in Boron neutron capture therapy (BNCT) and Hyperthermia for killing the tumor cell desired for the synthesis of a new kind of material suitable to be first used in BNCT and later on enable the conditions for Hyperthermia to destroy the tumor cell. The desire led to the synthesis of large band gap semiconductor nano-size Boron-10 enriched crystals of hexagonal boron nitride (10BNNCs). The contents of 10BNNCs are analyzed with the help of x-ray photoelectron spectroscopy (XPS) and counter checked with Raman and XRD. The 10B-contents in 10BNNCs produce 7Li and 4He nuclei. A Part of the 7Li and 4He particles released in the cell is allowed to kill the tumor (via BNCT) whereas the rest produce electron-hole pairs in the semiconductor layer of 10BNNCs suggested to work in Hyperthermia with an externally applied field.

Inhibiting Radiative Transition-Mediated Multifunctional Polymeric Nanoplatforms for Highly Efficient Tumor Phototherapeutics.

It is highly desired to explore ideal phototherapeutic nanoplatforms, especially containing satisfactory phototherapeutic agents (PTAs), for potential cancer therapies. Herein, we proposed an effective strategy for designing a highly efficient PTA through inhibiting radiative transition (IRT). Specifically, we developed an ultralow radiative BODIPY derivative (TPA-IBDP) by simply conjugating two triphenylamine units to iodine-substituted BODIPY, which could simultaneously facilitate the nonradiative decay channels of singlet-to-triplet intersystem crossing and intramolecular charge transfer. In comparison to the normal BODIPY compound, TPA-IBDP exhibited an outstanding singlet oxygen yield (31.8-fold) and a higher photothermal conversion efficiency (PCE; over 3-fold), respectively, benefiting from the extended π-conjugated donor-to-accepter (D-A) structure and the heavy atom effect. For tumor phototherapy using TPA-IBDP, TPA-IBDP was conjugated with a H2O2-responsive amphiphilic copolymer POEGMA10-b-[PBMA5-co-(PS-N3)2] to construct a multifunctional phototherapeutic BODIPY-based nanoplatform (PB). PB produced abundant singlet oxygen (1O2) and heat along with negligible fluorescence emission under near-infrared laser irradiation. Additionally, PB could generate a GSH-depletion scavenger (quinone methide, QM) after reacting with the abundant intracellular H2O2 in tumor for the cooperative enhancement of IRT-mediated phototherapy. We envision that this highly efficient multifunctional phototherapeutic nanoplatform cooperated by GSH-depletion could be a valuable paradigm for tumor treatments.