Photoacoustic Imaging Research Articles

Scalable Copper Sulfide Formulations for Super-Resolution Optoacoustic Brain Imaging in the Second Near-Infrared Window.

Optoacoustic imaging offers label-free multi-parametric characterization of cerebrovascular morphology and hemodynamics at depths and spatiotemporal resolution unattainable with optical microscopy. Effective imaging depth can greatly be enhanced by employing photons in the second near-infrared (NIR-II) window. However, diminished absorption by hemoglobin along with a lack of suitable contrast agents hinder an efficient application of the technique in this spectral range. Herein, copper sulfide (CuS) micro- and nano-formulations for multi-scale optoacoustic imaging in the NIR-II window are introduced. Dynamic contrast enhancement induced by intravenously administered CuS nanoparticles facilitated visualization of blood perfusion in murine cerebrovascular networks. The individual calcium carbonate microparticles carrying CuS are further shown to generate sufficient responses to enable super-resolution microvascular imaging and blood flow velocity mapping with localization optoacoustic tomography.

Biodegradable ICG-Conjugated Germanium Nanoparticles for In Vivo Near-Infrared Dual-Modality Imaging and Photothermal Therapy.

Theranostics, by integrating diagnosis and therapy on a single platform, enables real-time monitoring of tumors during treatment. To improve the accuracy of tumor diagnosis, the fluorescence and photoacoustic imaging modalities can complement each other to achieve high resolution and a deep penetration depth. Despite the superior performance, the biodegradability of theranostic agents plays a critical role in enhancing nanoparticle excretion and reducing chronic toxicity, which is essential for clinical applications. Herein, we synthesize biocompatible and biodegradable indocyanine green (ICG)-conjugated germanium nanoparticles (GeNPs) and investigate their biodistributions in nude mice and 4T1 tumor models after intravenous injections using near-infrared (NIR) dual-modality fluorescence and photoacoustic imaging. The ICG-conjugated GeNPs have strong NIR absorption due to the NIR-absorbing ICG and Ge in combination, emit strong NIR fluorescence due to the multilayered ICG coatings, and exhibit very low in vitro and in vivo toxicity. After tail vein injections, the ICG-conjugated GeNPs mainly accumulate in the liver and spleen as well as the tumor with the help of the enhanced permeability and retention effect. The tumor's fluorescence signal is much stronger than that of the control group injected with pure ICG solution, as the GeNPs can function as biodegradable carriers for efficiently delivering the ICG molecules to the tumor. Lastly, the ICG-conjugated GeNPs accumulated in the tumor can also be utilized for photothermal treatment under NIR laser irradiation, after which the tumor volume almost diminishes after 14 days. The experimental findings in this work demonstrate that the ICG-conjugated GeNPs are promising theranostic agents with exceptional biodegradability for in vivo NIR dual-modality imaging and photothermal therapy.

Responsive Theranostic Nanoprobe for Ratiometric Photoacoustic Monitoring of Hypochlorous Acid‐Mediated Inflammation in Cancer Photothermal Therapy

AbstractCancer detection and inflammation monitoring during photothermal therapy (PTT) enable timely cancer intervention and precise inflammation control, advancing to address inflammation‐related tumor recurrence and metastasis associated with PTT. This can be achieved through real‐time monitoring biomarker for cancer and inflammation, like hypochlorous acid (HOCl), a highly reactive oxygen species (hROS) in body with elevated levels in inflammation. Here, a HOCl‐responsive theranostic nanoprobe is introduced, AuNRs@SiO2‐CAA for ratiometric photoacoustic (PA) cancer detection and inflammation monitoring during PTT. AuNRs@SiO2‐CAA emits PA signals at 680 and 820 nm, with only PA680 undergoing changes in the presence of HOCl, enabling precise HOCl imaging via recording changes of ratiometric PA signals (PA680/PA820). AuNRs@SiO2‐CAA exhibits high selectivity and sensitivity, with a detection limit of 0.34 µM for ratiometric PA imaging of HOCl. In vivo, it effectively detects tumor, drives PTT, and monitors inflammation during PTT by sensing HOCl. The successful development of AuNRs@SiO2‐CAA offers a novel theranostic nanoprobe system for cancer diagnosis, poised to enhance PTT through precise inflammation control.

3-D Visualization of Atlantic salmon skin through Ultrasound and Photoacoustic Microscopy.

Three-dimensional photoacoustic imaging (PAM) has emerged as a promising technique for non-invasive label-free visualization and characterization of biological tissues with high spatial resolution and functional contrast. The application of PAM and ultrasound as a microscopy technique of study for Atlantic salmon skin is presented here. A custom ultrasound and photoacoustic experimental setup was used for conducting this experiment with a sample preparation method where the salmon skin is embedded in agarose and lifted from the bottom of the petridish. The results of C-scan, B-scan, and overlayed images of ultrasound and photoacoustic are presented. The results are then analyzed for understanding the pigment map and its relation to salmon behavior to external stimuli. The photoacoustic images are compared with the optical images and analyzed further. A custom colormap and alpha map is designed and the matrices responsible for PAM and ultrasound are inserted together to overlay the ultrasound image and PAM image on top of each other. In this study, we propose an approach that combines scanning acoustic microscopy (SAM) images with PAM images for providing a comprehensive understanding of the salmon skin tissue. Overlaying acoustic and photoacoustic images enabled unique visualization of tissue morphology, with respect to identification of structural features in the context of their pigment distribution.

Robotically steerable intraluminal imaging probe with side-viewing 3D photoacoustic computed tomography

This Letter presents, for the first time to our knowledge, a continuum robotic-steered endoluminal volumetric photoacoustic tomography probe. With regard to the design of the probe, a coaxial optical and acoustic imaging system has been developed that employs a custom designed piezoelectric micromachined ultrasonic transducer (PMUT). The dimensions of the system are constrained within a cylindrical housing with a diameter of 12 mm and a length of 30 mm. In regard to the robot design, the motion capabilities of the continuum robot have been successfully modeled and characterized. Based on the proposed system, the potential for early detection and screening of gastrointestinal cancers through phantoms has been validated. The experimental results demonstrate that the robotic-assisted photoacoustic system performs well in localizing unknown lesions and characterizing deep-seated abnormalities, exhibiting promising clinical applications.

Photoacoustic Waveform Design for Optimal Parameter Estimation Based on Maximum Mutual Information

Waveform design is a potentially significant approach to improve the performance of an imaging or detection system. Photoacoustic imaging is a rapidly developing field in recent years; however, photoacoustic waveform design has not been extensively investigated. This paper considers the problem of photoacoustic waveform design for parameter estimation under constraints on input energy. The use of information theory is exploited to formulate and solve this optimal waveform design problem. The approach yields the optimal waveform power spectral density. Direct inverse Fourier transform of the optimal waveform frequency spectrum amplitude is proposed to obtain a real waveform in the time domain. Absorbers are assumed to be stochastic absorber ensembles with uncertain duration and location parameters. Simulation results show the relationship between absorber parameter distribution and the characteristics of optimal waveforms. Comparison of optimal waveforms for estimation, optimal waveforms for detection (signal-to-noise ratio) and other commonly used waveforms are also discussed. The symmetry properties of the forward and inverse Fourier Transforms are used to analyze the time and frequency properties and provide a heuristic view of how different goals affect the choice of waveform.

Enhanced optical nonlinearity in suspensions of dual-resonance gold–copper chalcogenide core–shell nanoparticles

Plasmonic copper chalcogenide (Cu2−xE, E = S, Se, Te) nanoparticles (NPs) possess high potentials in photothermal therapy and photoacoustic tomography for their unique localized surface plasmon resonant absorption in the second near-infrared biologically transparent window. In this study, strong thermal-induced nonlinear negative-lens effect in aqueous suspensions containing Cu2−xSe NPs was observed. Furthermore, the nonlinear absorption was notably enhanced in aqueous suspensions containing Au@Cu2−xSe core–shell NPs, as the positive nonlinear absorption coefficient increased by 20-fold, attributed to the strong plasmonic coupling in Au@Cu2−xSe core–shell NPs. This finding underscores the importance of the nonlinear optical behaviors of plasmonic NPs in biomedical applications, as they offer extra strategy for optimizing systems and incorporating additional functionalities.

Histological and photoacoustic evaluation of rectal cancer after neoadjuvant therapy using microvascular density.

As non-operative management of rectal cancer proliferates, re-staging and surveillance methods are critical in selecting appropriate patients for organ preservation versus proctectomy. In previous work, the authors have shown that transrectal acoustic resolution photoacoustic microscopy (ARPAM) co-registered with ultrasound can differentiate residual cancer from complete tumoural response to neoadjuvant therapy. We hypothesize that these findings are due to changes in microvascular density (MVD). Patients with rectal adenocarcinoma who underwent neoadjuvant therapy, transrectal photoacoustic imaging and resection were included. We first compared immunohistochemical staining with erythroblast transformation-specific-related gene (ERG) immunostain to standard CD31 to confirm adequate identification of endothelium. Tissue sections from identical blocks were stained with CD31 and ERG, and then a correlation was calculated between manually labelled CD31-stained vessels and ERG nuclei density. Second, representative tissue blocks from responders, partial responders and non-responders were stained with ERG. ERG nuclei density was quantified as a proxy for MVD. CD31 MVD and ERG nuclei density were strongly correlated (R2 = 0.87; P < 0.01). In the tumour bed of patients after neoadjuvant therapy, MVD of complete responders (599 nuclei/mm2; 95% CI 434-764) is significantly higher (P < 0.01) than that of partial responders (185 nuclei/mm2; 95% CI 64-306) and non-responders (117 nuclei/mm2; 95% CI 42-192). No significant difference was found between the partial responders and non-responders (P = 0.60). Microvascular density appears highest in cases of complete tumour response to neoadjuvant therapy, similar to normal rectal tissue. The histological microvascular patterns seen in treated tissue may explain the imaging patterns seen in photoacoustic microscopy.

Dual Enzyme-Driven Cascade Reactions Modulate Immunosuppressive Tumor Microenvironment for Catalytic Therapy and Immune Activation.

Lactate-enriched tumor microenvironment (TME) fosters an immunosuppressive milieu to hamper the functionality of tumor-associated macrophages (TAMs). However, tackling the immunosuppressive effects wrought by lactate accumulation is still a big challenge. Herein, we construct a dual enzyme-driven cascade reaction platform (ILH) with immunosuppressive TME modulation for photoacoustic (PA) imaging-guided catalytic therapy and immune activation. The ILH is composed of iridium (Ir) metallene nanozyme, lactate oxidase (LOx), and hyaluronic acid (HA). The combination of Ir nanozyme and LOx can not only efficiently consume lactate to reverse the immunosuppressive TME into an immunoreactive one by promoting the polarization of TAMs from the M2 to M1 phenotype, thus enhancing antitumor defense, but also alleviate tumor hypoxia as well as induce strong oxidative stress, thus triggering immunogenic cell death (ICD) and activating antitumor immunity. Furthermore, the photothermal performance of Ir nanozyme can strengthen the cascade catalytic ability and endow ILH with a PA response. Based on the changes in PA signals from endogenous molecules, three-dimensional multispectral PA imaging was utilized to track the process of cascade catalytic therapy in vivo. This work provides a nanoplatform for dual enzyme-driven cascade catalytic therapy and immune activation by regulating the immunosuppressive TME.

Highly Amplified Broadband Ultrasound in Antiresonant Hollow Core Fibers

High‐frequency broadband ultrasound in nested antiresonant hollow core fibers (NANFs) is investigated for the first time. NANFs have remarkable features enabling high‐resolution microscale optoacoustic imaging sensors and neurostimulators. Solid optical fibers have been successfully employed to measure and generate ultrasonic signals, however, they face issues concerning attenuation, limited frequency range, bandwidth, and spatial resolution. Herein, highly efficient ultrasonic propagation in NANFs from 10 to 100 MHz is numerically demonstrated. The induced pressures and sensing responsivity are evaluated in detail, and important parameters for the development of ultrasonic devices are reviewed. High pressures (up to 234 MPa) and sensing responsivities (up to −207 dB) are tuned over 90 MHz range by changing the diameters of two distinct NANF geometries. To the best of knowledge, this is the widest bandwidth reported using similar diameter fibers. The results are a significant advance for fiber‐based ultrasonic sensors and transmitters, contributing to improve their efficiency and microscale spatial resolution for the detection, diagnosis, and treatment of diseases in biomedical applications.

Advanced deep-tissue imaging and manipulation enabled by biliverdin reductase knockout.

We developed near-infrared (NIR) photoacoustic and fluorescence probes, as well as optogenetic tools from bacteriophytochromes, and enhanced their performance using biliverdin reductase-A knock-out model (Blvra-/-). Blvra-/- elevates endogenous heme-derived biliverdin chromophore for bacteriophytochrome-derived NIR constructs. Consequently, light-controlled transcription with IsPadC-based optogenetic tool improved up to 25-fold compared to wild-type cells, with 100-fold activation in Blvra-/- neurons. In vivo , light-induced insulin production in Blvra-/- reduced blood glucose in diabetes by ∼60%, indicating high potential for optogenetic therapy. Using 3D photoacoustic, ultrasound, and two-photon fluorescence imaging, we overcame depth limitations of recording NIR probes. We achieved simultaneous photoacoustic imaging of DrBphP in neurons and super-resolution ultrasound localization microscopy of blood vessels ∼7 mm deep in the brain, with intact scalp and skull. Two-photon microscopy provided cell-level resolution of miRFP720-expressing neurons ∼2.2 mm deep. Blvra-/- significantly enhances efficacy of biliverdin-dependent NIR systems, making it promising platform for interrogation and manipulation of biological processes.

Enhancing the tissue penetration to improve sonodynamic immunotherapy for pancreatic ductal adenocarcinoma using membrane-camouflaged nanoplatform.

Sonodynamic therapy (SDT) is a promising strategy as an "in situ vaccine" to enhance activation of antitumor immune responses in solid tumors. However, the dense extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) lead to hypoxia and limited penetration of most drugs, aggravating the immunosuppressive tumor microenvironment and limiting the efficacy of synergistic sonodynamic immunotherapy. Therefore, it is essential to regulate ECM in order to alleviate tumor hypoxia and enhance the efficacy of sonodynamic immunotherapy for PDAC. The CPIM nanoplatform, consisting of a macrophage membrane-coated oxygen and drug delivery system (CM@PFOB-ICG-α-Mangostin), was synthesized using ultrasound and extrusion methods. The in vivo homologous targeting and hypoxia alleviation capabilities of CPIM were evaluated through near-infrared (NIR) imaging and photoacoustic (PA) imaging. The tumor growth inhibition potential and ability to reprogram the tumor microenvironment by the CPIM nanoplatform were also investigated. Co-delivery of α-Mangostin inhibits CAFs and enhances stromal depletion, thereby facilitating better infiltration of macromolecules. Additionally, the nanoemulsion containing perfluorocarbon (PFC) can target tumor cells and accumulate within them through homologous targeting. The US irradiation results in the rapid release of oxygen, serving as a potential source of sonodynamic therapy for hypoxic tumors. Moreover, CPIM reshapes the immunosuppressive microenvironment increasing the population of cytotoxic T lymphocytes (CTLs), and enhancing their anti-tumor immune response through the use of anti-PDL1 antibodies to block immune checkpoints. The present study offers a potential strategy for the co-delivery of oxygen and α-Mangostin, aiming to enhance the penetration of tumors to improve SDT. This approach effectively addresses the existing limitations of immune checkpoint blockade (ICB) treatment in solid tumors, while simultaneously boosting the immune response through synergistic sonodynamic immunotherapy.

Carrier-Free Biomimetic Organic Nanoparticles with Super-High Drug Loading for Targeted NIR-II Excitable Triple-Modal Bioimaging and Phototheranostics.

Multimodal near-infrared II (NIR-II) theranostics combined with nanotechnology have emerged as promising treatments for cancer due to their noninvasive and high spatiotemporal nature. Traditional NIR-II theranostics typically comprise useless and massive inert carriers, resulting in low drug loading capacity, reduced therapeutic effects, and potential biotoxicity. To overcome these limitations, this work reports carrier-free NIR-II theranostics simultaneously with high drug loading capacity and multimodal NIR-II imaging capabilities for cancer phototheranostics in the NIR-II window. Carrier-free BTA nanoparticles (NPs) are prepared by self-assembling the NIR-II responsive conjugated oligomer BTA without adding coating agents; these NPs exhibited 100% drug loading and high-performance NIR-II theranostic capabilities. Cancer cell membranes are camouflaged on carrier-free BTA NPs to provide homologous targeting ability, enhanced stability, and 77.8% drug loading. Both in vitro and in vivo studies have indicated that biomimetic NPs provide efficient triple-modal guidance for NIR-II fluorescence, photoacoustic, and photothermal imaging and complete tumor elimination via photothermal therapy (PTT). Additionally, theranostics-based treatments with good biosecurity are demonstrated. This study contributes a new strategy for the design of high-drug-loading NIR-II theranostics and further promotes the clinical translation of theranostic agents.

Enhancing image reconstruction in Enhancing image reconstruction in photoacoustic imaging using spatial coherence mean-to-standard-deviation factor beamformingphotoacoustic imaging using spatial coherence mean-to-standard-deviation factor beamforming

Enhancing image reconstruction in Enhancing image reconstruction in photoacoustic imaging using spatial coherence mean-to-standard-deviation factor beamformingphotoacoustic imaging using spatial coherence mean-to-standard-deviation factor beamforming

Performance evaluation of image co-registration methods in photoacoustic mesoscopy of the vasculature

Objective:The formation of functional vasculature in solid tumours enables delivery of oxygen and nutrients, and is vital for effective treatment with chemotherapeutic agents. Longitudinal characterisation of vascular networks can be enabled using mesoscopic photoacoustic imaging, but requires accurate image co-registration to precisely assess local changes across disease development or in response to therapy. Co-registration in photoacoustic imaging is challenging due to the complex nature of the generated signal, including the sparsity of data, artefacts related to the illumination/detection geometry, scan-to-scan technical variability, and biological variability, such as transient changes in perfusion. To better inform the choice of co-registration algorithms, we compared five open-source methods, in physiological and pathological tissues, with the aim of aligning evolving vascular networks in tumours imaged over growth at different time-points.Approach:Co-registration techniques were applied to 3D vascular images acquired with photoacoustic mesoscopy from murine ears and breast cancer patient-derived xenografts, at a fixed time-point and longitudinally. Images were pre-processed and segmented using an unsupervised generative adversarial network. To compare co-registration quality in different settings, pairs of fixed and moving intensity images and/or segmentations were fed into five methods split into the following categories: affine intensity-based using 1)mutual information (MI) or 2)normalised cross-correlation (NCC) as optimisation metrics, affine shape-based using 3)NCC applied to distance-transformed segmentations or 4)iterative closest point algorithm, and deformable weakly supervised deep learning-based using 5)LocalNet co-registration. Percent-changes in Dice coefficients, surface distances, MI, structural similarity index measure and target registration errors were evaluated.Main results:Co-registration using MI or NCC provided similar alignment performance, better than shape-based methods. LocalNet provided accurate co-registration of substructures by optimising subfield deformation throughout the volumes, outperforming other methods, especially in the longitudinal breast cancer xenograft dataset by minimising target registration errors.Significance:We showed the feasibility of co-registering repeatedly or longitudinally imaged vascular networks in photoacoustic mesoscopy, taking a step towards longitudinal quantitative characterisation of these complex structures. These tools open new outlooks for monitoring tumour angiogenesis at the meso-scale and for quantifying treatment-induced co-localised alterations in the vasculature.

Multimodal Photoacoustic/Elastography Imaging for the Detection of Acute Radiation Dermatitis in Breast Radiation Therapy

Purpose: This study evaluates whether photoacoustic (PA), sound touch elastography (STE), and viscoelasticity (VE) can distinguish between normal and abnormal post-radiotherapy breast skin and compare these methods with RTOG criteria at a 20 Gy threshold. Methods: Patients meeting inclusion and exclusion criteria underwent PA, STE, and VE on the same day. Collected data included radiation dose, molecular type, RTOG, Fitzpatrick skin type, pathology, neoadjuvant chemotherapy status, TNM classification, surgical procedures, primary breast cancer location, BMI, and age. A sample of 41 patients was determined using a two-sample t-test. Statistical tools like T-tests, variance analysis, rank sum tests, and chi-square tests, along with random forest analysis and ROC curves, were used to evaluate the radiation dose effects. Results: Data from 66 patients showed significant differences in parameters such as dermis and subcutaneous tissue oxygen saturation, dermal thickness, and skin elasticity (p-values < 0.05). However, minimum values of oxygen saturation and some photoacoustic measures were not significantly different. Notably, at a 20 Gy radiation threshold, significant variations in oxygen saturation, abnormal dermal thickness, and skin STE and VE were observed, proving more accurate than RTOG grading. Conclusion: The study confirms the effectiveness of PA and elastography imaging in differentiating normal from abnormal breast tissue and assessing radiation-induced changes, highlighting the potential of these imaging techniques.

Noninvasive high-resolution deep-brain photoacoustic imaging with negatively-focused fiber-laser ultrasound transducer

Noninvasive high-resolution deep-brain photoacoustic imaging with negatively-focused fiber-laser ultrasound transducer

Reshaping Immunosuppressive Tumor Microenvironment Using Ferroptosis/Cuproptosis Nanosensitizers for Enhanced Radioimmunotherapy

AbstractRadiotherapy, a traditional cancer treatment, not only controls local tumor growth but also potentially induces immunogenic cell death, initiating systemic immune responses. However, radiotherapy resistance and immunosuppressive tumor microenvironments often limit the potency of radiation‐induced anti‐tumor immune responses, rendering them insufficient for clinical applications. Consequently, trimetallic nanoparticles are constructed with dual enzymatic activity, AuBiCu‐distearoyl phosphoethanolamine‐PEG nanoparticles (AuBiCu‐PEG NPs), to synergistically improve radiotherapy resistance through X‐ray deposition, hypoxia alleviation, and ferroptosis and cuproptosis induction. This approach promotes radiotherapy‐induced immunogenic cell death and boosts anti‐tumor immune responses. Furthermore, AuBiCu‐PEG NPs effectively reversed radiation‐induced upregulation of programmed cell death 1 ligand 1 (PD‐L1), inhibit tumor immune evasion, and reshaped the immune microenvironment. Non‐invasive and real‐time longitudinal monitoring of nanoparticle accumulation in tumors can be achieved using spectral computed tomography (CT) and photoacoustic (PA) imaging. In summary, the designed AuBiCu‐PEG NPs serve as promising nanoplatforms for immune microenvironment remodeling and can be used in multimodal molecular imaging‐guided ferroptosis‐cuproptosis‐enhanced radiotherapy.

Nanoporous Submicron Gold Particles Enable Nanoparticle-Based Localization Optoacoustic Tomography (nanoLOT).

Localization optoacoustic tomography (LOT) has recently emerged as a transformative super-resolution technique breaking through the acoustic diffraction limit in deep-tissue optoacoustic (OA) imaging via individual localization and tracking of particles in the bloodstream. However, strong light absorption in red blood cells has previously restricted per-particle OA detection to relatively large microparticles, ≈5µm in diameter. Herein, it is demonstrated that submicron-sized porous gold nanoparticles, ≈600nm in diameter, can be individually detected for noninvasive super-resolution imaging with LOT. Ultra-high-speed bright-field microscopy revealed that these nanoparticles generate microscopic plasmonic vapor bubbles, significantly enhancing opto-acoustic energy conversion through a nano-to-micro size transformation. Comprehensive in vitro and in vivo tests further demonstrated the biocompatibility and biosafety of the particles. By reducing the detectable particle size by an order of magnitude, nanoLOT enables microangiographic imaging with a significantly reduced risk of embolisms from particle aggregation and opens new avenues to visualize how nanoparticles reach vascular and potentially extravascular targets. The performance of nanoLOT for non-invasive imaging of microvascular networks in the murine brain anticipates new insights into neurovascular coupling mechanisms and longitudinal microcirculatory changes associated with neurodegenerative diseases.

Finely tunable NIR‐II organic scaffolds for fluorescence/photoacoustic duplex imaging–guided noninvasive photothermal therapy of glioblastoma

AbstractOrganic agents possessing NIR‐II and photoacoustic duplex imaging capabilities, coupled with high‐efficiency photothermal conversion, offer significant potential for noninvasive and precise phototheranostics of glioblastoma, which is further augmented when these agents can concurrently exhibit tumor targeting and blood–brain barrier (BBB) permeability. This study reports a series of finely tunable NIR‐II molecular luminophores based on the aza‐BODIPY scaffold, featuring unique twisted and rotatable structures. They are further constructed to folate‐decorated polymeric nanoparticles, exhibiting remarkable NIR‐II/photoacoustic imaging performance and superior photothermal conversion efficiency (49.7%). Folate modification enables tumor targeting and BBB permeability through receptor‐mediated transcytosis, allowing for precise and efficient phototherapy in 4T1‐/glioblastoma‐bearing mice after a single intravenous injection and irradiation. This study presents a rational molecular engineering approach and a versatile structural scaffold for designing NIR‐II emitters with tailored photophysical properties and desirable phototherapeutic efficacy, thereby offering novel perspectives on the development of advanced depth imaging probes and brain tumor therapeutics.