A Self‐Assembled Biocompatible Nanoplatform for Multimodal MR/Fluorescence Imaging Assisted Photothermal Therapy and Prognosis Analysis

The need for better imaging assisted cancer therapy calls for new biocompatible agents with excellent imaging and therapeutic capabilities. This study successfully fabricates albumin‐cooperated human serum albumin (HSA)‐GGD‐ICG nanoparticles (NPs), which are comprised of a magnetic resonance (MR) contrast agent, glycyrrhetinic‐acid‐modified gadolinium (III)‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate (GGD), and a fluorescence (FL) dye, indocyanine green (ICG), for multimodal MR/FL imaging assisted cancer therapy. These HSA‐GGD‐ICG NPs with excellent biocompatibility are stable under physiological conditions, and exhibit enhanced T₁ contrast capability and improved fluorescence imaging capacity. In vitro experiments reveal an apparent effect of the NPs in killing tumor cells under low laser irradiation, due to the enhanced photothermal conversion efficiency (≈85.1%). Importantly, multimodal MR/FL imaging clearly shows the in vivo behaviors and the efficiency of tumor accumulation of HSA‐GGD‐ICG NPs, as confirmed by a pharmacokinetic study. With the guidance of multimodal imaging, photothermal therapy is subsequently conducted, which demonstrates again high photothermal conversion capability for eliminating tumors without relapse. Notably, real‐time monitoring of tumor ablation for prognosis and therapy evaluation is also achieved by MR imaging. This strategy of constructing nanoplatforms through albumin‐mediated methods is both convenient and efficient, which would enlighten the design of multimodal imaging assisted cancer therapy for potential clinical translation.     

Core–Satellite Polydopamine–Gadolinium‐Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging‐guided therapy. However, most gadolinium (Gd)–chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released‐Gd‐ions‐associated toxicity. Herein, a radionuclide‐⁶⁴Cu‐labeled doxorubicin‐loaded polydopamine (PDA)–gadolinium‐metallofullerene core–satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging‐guided combination cancer therapy. In this system, the near‐infrared (NIR)‐absorbing PDA acts as a platform for the assembly of different moieties; Gd₃N@C₈₀, a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as‐prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r ₁ = 14.06 mM^?1 s^?1), low risk of release of Gd ions, and NIR‐triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo‐photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.     

Fluorescence Quenching Nanoprobes Dedicated to In Vivo Photoacoustic Imaging and High‐Efficient Tumor Therapy in Deep‐Seated Tissue

Photoacoustic imaging (PAI) and photoacoustic (PA) therapy have promising applications for treating tumors. It is known that the utilization of high‐absorption‐coefficient probes can selectively enhance the PAI target contrast and PA tumor therapy efficiency in deep‐seated tissue. Here, the design of a probe with the highest availability of optical‐thermo conversion by using graphene oxide (GO) and dyes via π–π stacking interactions is reported. The GO serves as a base material for loading dyes and quenching dye fluorescence via fluorescence resonance energy transfer (FRET), with the one purpose of maximum of PA efficiency. Experiments verify that the designed fluorescence quenching nanoprobes can produce stronger PA signals than the sum of the separate signals generated in the dye and the GO. Potential applications of the fluorescence quenching nanoprobes are demonstrated, dedicating to enhance PA contrast of targets in deep‐seated tissues and tumors in living mice. PA therapy efficiency both in vitro and in vivo by using the fluorescence quenching nanoprobes is found to be higher than with the commonly used PA therapy agents. Taken together, quenching dye fluorescence via FRET will provide a valid means for developing high‐efficiency PA probes. Fluorescence quenching nanoprobes are likely to become a promising candidate for deep‐seated tumor imaging and therapy.     

Guiding Brain‐Tumor Surgery via Blood–Brain‐Barrier‐Permeable Gold Nanoprobes with Acid‐Triggered MRI/SERRS Signals

Surgical resection is a mainstay in the treatment of malignant brain tumors. Surgeons, however, face great challenges in distinguishing tumor margins due to their infiltrated nature. Here, a pair of gold nanoprobes that enter a brain tumor by crossing the blood–brain barrier is developed. The acidic tumor environment triggers their assembly with the concomitant activation of both magnetic resonance (MR) and surface‐enhanced resonance Raman spectroscopy (SERRS) signals. While the bulky aggregates continuously trap into the tumor interstitium, the intact nanoprobes in normal brain tissue can be transported back into the blood stream in a timely manner. Experimental results show that physiological acidity triggers nanoparticle assembly by forming 3D spherical nanoclusters with remarkable MR and SERRS signal enhancements. The nanoprobes not only preoperatively define orthotopic glioblastoma xenografts by magnetic resonance imaging (MRI) with high sensitivity and durability in vivo, but also intraoperatively guide tumor excision with the assistance of a handheld Raman scanner. Microscopy studies verify the precisely demarcated tumor margin marked by the assembled nanoprobes. Taking advantage of the nanoprobes' rapid excretion rate and the extracellular acidification as a hallmark of solid tumors, these nanoprobes are promising in improving brain‐tumor surgical outcome with high specificity, safety, and universality.     

Semiconducting Polymer Nanoparticles for Centimeters‐Deep Photoacoustic Imaging in the Second Near‐Infrared Window

Thienoisoindigo‐based semiconducting polymer with a strong near‐infrared absorbance is synthesized and its water‐dispersed nanoparticles (TSPNs) are investigated as a contrast agent for photoacoustic (PA) imaging in the second near‐infrared (NIR‐II) window (1000–1350 nm). The TSPNs generate a strong PA signal in the NIR‐II optical window, where background signals from endogenous contrast agents, including blood and lipid, are at the local minima. By embedding a TSPN‐containing tube in chicken‐breast tissue, an imaging depth of more than 5 cm at 1064 nm excitation is achieved with a contrast‐agent concentration as low as 40 µg mL^?1. The TSPNs under the skin or in the tumor are clearly visualized at 1100 and 1300 nm, with negligible interference from the tissue background. TSPN as a PA contrast in the NIR‐II window opens new opportunities for biomedical imaging of deep tissues with improved contrast.     

Dual‐Modality Surface‐Enhanced Resonance Raman Scattering and Multispectral Optoacoustic Tomography Nanoparticle Approach for Brain Tumor Delineation

Difficulty in visualizing glioma margins intraoperatively remains a major issue in the achievement of gross total tumor resection and, thus, better clinical outcome of glioblastoma (GBM) patients. Here, the potential of a new combined optical + optoacoustic imaging method for intraoperative brain tumor delineation is investigated. A strategy using a newly developed gold nanostar synthesis method, Raman reporter chemistry, and silication method to produce dual‐modality contrast agents for combined surface‐enhanced resonance Raman scattering (SERRS) and multispectral optoacoustic tomography (MSOT) imaging is devised. Following intravenous injection of the SERRS‐MSOT‐nanostars in brain tumor bearing mice, sequential MSOT imaging is performed in vivo and followed by Raman imaging. MSOT is able to accurately depict GBMs three‐dimensionally with high specificity. The MSOT signal is found to correlate well with the SERRS images. Because SERRS enables uniquely sensitive high‐resolution surface detection, it could represent an ideal complementary imaging modality to MSOT, which enables real‐time, deep tissue imaging in 3D. This dual‐modality SERRS‐MSOT‐nanostar contrast agent reported here is shown to enable high precision depiction of the extent of infiltrating GBMs by Raman‐ and MSOT imaging in a clinically relevant murine GBM model and could pave new ways for improved image‐guided resection of brain tumors.     

Metabolizable Semiconducting Polymer Nanoparticles for Second Near‐Infrared Photoacoustic Imaging

Photoacoustic (PA) imaging in the second near‐infrared (NIR‐II) window (1000–1700 nm) holds great promise for deep‐tissue diagnosis due to the reduced light scattering and minimized tissue absorption; however, exploration of such a noninvasive imaging technique is greatly constrained by the lack of biodegradable NIR‐II absorbing agents. Herein, the first series of metabolizable NIR‐II PA agents are reported based on semiconducting polymer nanoparticles (SPNs). Such completely organic nanoagents consist of π‐conjugated yet oxidizable optical polymer as PA generator and hydrolyzable amphiphilic polymer as particle matrix to provide water solubility. The obtained SPNs are readily degraded by myeloperoxidase and lipase abundant in phagocytes, transforming from nonfluorescent nanoparticles (30 nm) into NIR fluorescent ultrasmall metabolites (≈1 nm). As such, these nanoagents can be effectively cleared out via both hepatobiliary and renal excretions after systematic administration, leaving no toxicity to living mice. Particularly these nanoagents possess high photothermal conversion efficiencies and emit bright PA signals at 1064 nm, enabling sensitive NIR‐II PA imaging of both subcutaneous tumor and deep brain vasculature through intact skull in living animals at a low systematic dosage. This study thus provides a generalized molecular design toward organic metabolizable semiconducting materials for biophotonic applications in NIR‐II window.     

Photoacoustic Imaging: Contrast Agents and Their Biomedical Applications

Photoacoustic (PA) imaging as a fast‐developing imaging technique has great potential in biomedical and clinical applications. It is a noninvasive imaging modality that depends on the light‐absorption coefficient of the imaged tissue and the injected PA‐imaging contrast agents. Furthermore, PA imaging provides superb contrast, super spatial resolution, and high penetrability and sensitivity to tissue functional characteristics by detecting the acoustic wave to construct PA images. In recent years, a series of PA‐imaging contrast agents are developed to improve the PA‐imaging performance in biomedical applications. Here, recent progress of PA contrast agents and their biomedical applications are outlined. PA contrast agents are classified according to their components and function, and gold nanocrystals, gold‐nanocrystal assembly, transition‐metal chalcogenides/MXene‐based nanomaterials, carbon‐based nanomaterials, other inorganic imaging agents, small organic molecules, semiconducting polymer nanoparticles, and nonlinear PA‐imaging contrast agents are discussed. The applications of PA contrast agents as biosensors (in the sensing of metal ions, pH, enzymes, temperature, hypoxia, reactive oxygen species, and reactive nitrogen species) and in bioimaging (lymph nodes, vasculature, tumors, and brain tissue) are discussed in detail. Finally, an outlook on the future research and investigation of PA‐imaging contrast agents and their significance in biomedical research is presented.     

Light‐Responsive Biodegradable Nanorattles for Cancer Theranostics

Cancer nanotheranostics, integrating both diagnostic and therapeutic functions into nanoscale agents, are advanced solutions for cancer management. Herein, a light‐responsive biodegradable nanorattle‐based perfluoropentane‐(PFP)‐filled mesoporous‐silica‐film‐coated gold nanorod (GNR@SiO₂‐PFP) is strategically designed and prepared for enhanced ultrasound (US)/photoacoustic (PA) dual‐modality imaging guided photothermal therapy of melanoma. The as‐prepared nanorattles are composed of a thin mesoporous silica film as the shell, which endows the nanoplatform with flexible morphology and excellent biodegradability, as well as large cavity for PFP filling. Upon 808 nm laser irradiation, the loaded PFP will undergo a liquid–gas phase transition due to the heat generation from GNRs, thus generating nanobubbles followed by the coalescence into microbubbles. The conversion of nanobubbles to microbubbles can improve the intratumoral permeation and retention in nonmicrovascular tissue, as well as enhance the tumor‐targeted US imaging signals. This nanotheranostic platform exhibits excellent biocompatibility and biodegradability, distinct gas bubbling phenomenon, good US/PA imaging contrast, and remarkable photothermal efficiency. The results demonstrate that the GNR@SiO₂‐PFP nanorattles hold great potential for cancer nanotheranostics.     

Enhanced Performance of a Molecular Photoacoustic Imaging Agent by Encapsulation in Mesoporous Silicon Nanoparticles

Photoacoustic (PA) imaging allows visualization of the physiology and pathology of tissues with good spatial resolution and relatively deep tissue penetration. The method converts near‐infrared (NIR) laser excitation into thermal expansion, generating pressure transients that are detected with an acoustic transducer. Here, we find that the response of the PA contrast agent indocyanine green (ICG) can be enhanced 17‐fold when it is sealed within a rigid nanoparticle. ICG encapsulated in particles composed of porous silicon (pSiNP), porous silica, or calcium silicate all show greater PA contrast relative to equivalent quantities of free ICG, with the pSiNPs showing the strongest enhancement. A liposomal formulation of ICG performs similar to free ICG, suggesting that a rigid host nanostructure is necessary to enhance ICG performance. The improved response of the nanoparticle formulations is attributed to the low thermal conductivity of the porous inorganic hosts and their ability to protect the ICG payload from photolytic and/or thermal degradation. The translational potential of ICG‐loaded pSiNPs as photoacoustic probes is demonstrated via imaging of a whole mouse brain.     

Structure‐Guided Design and Synthesis of a Mitochondria‐Targeting Near‐Infrared Fluorophore with Multimodal Therapeutic Activities

An urgent challenge for imaging‐guided disease‐targeted multimodal therapy is to develop the appropriate multifunctional agents to meet the requirements for potential applications. Here, a rigid cyclohexenyl substitution in the middle of a polymethine linker and two asymmetrical amphipathic N‐alkyl side chains to indocyanine green (ICG) (the only FDA‐approved NIR contrast agent) are introduced, and a new analog, IR‐DBI, is developed with simultaneous cancer‐cell mitochondrial targeting, NIR imaging, and chemo‐/PDT/PTT/multimodal therapeutic activities. The asymmetrical and amphipathic structural modification renders IR‐DBI a close binding to albumin protein site II to form a drug–protein complex and primarily facilitates its preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. The released IR‐DBI dye is further actively taken up by cancer cells through organic‐anion‐transporting polypeptide transporters, and the lipophilic cationic property leads to its selective accumulation in the mitochondria of cancer cells. Finally, based on the high albumin‐binding affinity, IR‐DBI is modified into human serum albumin (HSA) via self‐assembly to produce a nanosized complex, which exhibits significant improvement in the cancer targeting and multimodal cancer treatment with better biocompatibility. This finding may present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer diagnostics and therapeutics.     

Molecular Cancer Imaging in the Second Near‐Infrared Window Using a Renal‐Excreted NIR‐II Fluorophore‐Peptide Probe

In vivo molecular imaging of tumors targeting a specific cancer cell marker is a promising strategy for cancer diagnosis and imaging guided surgery and therapy. While targeted imaging often relies on antibody‐modified probes, peptides can afford targeting probes with small sizes, high penetrating ability, and rapid excretion. Recently, in vivo fluorescence imaging in the second near‐infrared window (NIR‐II, 1000–1700 nm) shows promise in reaching sub‐centimeter depth with microscale resolution. Here, a novel peptide (named CP) conjugated NIR‐II fluorescent probe is reported for molecular tumor imaging targeting a tumor stem cell biomarker CD133. The click chemistry derived peptide‐dye (CP‐IRT dye) probe afforded efficient in vivo tumor targeting in mice with a high tumor‐to‐normal tissue signal ratio (T/NT > 8). Importantly, the CP‐IRT probes are rapidly renal excreted (≈87% excretion within 6 h), in stark contrast to accumulation in the liver for typical antibody‐dye probes. Further, with NIR‐II emitting CP‐IRT probes, urethra of mice can be imaged fluorescently for the first time noninvasively through intact tissue. The NIR‐II fluorescent, CD133 targeting imaging probes are potentially useful for human use in the clinic for cancer diagnosis and therapy.     

Active Targeting Using HER‐2‐Affibody‐Conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER‐2 Positive Ovarian Tumors

Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER‐2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER‐2 affibody that is labeled with a unique near infrared dye (NIR‐830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER‐2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non‐invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER‐2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER‐2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non‐targeted IONPs into the mice bearing HER‐2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER‐2 low expressing OVCAR3 tumors after systemic delivery of HER‐2 targeted‐IONPs. Since HER‐2 is expressed in a high percentage of ovarian cancers, the HER‐2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image‐guided therapy and surgery.     

Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image‐Guided Surgery via NIR‐II Fluorescence and PET Bimodal Imaging

Bimodal imaging with fluorescence in the second near infrared window (NIR‐II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR‐II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR‐II dye CH‐4T, and PET radionuclide ⁶⁴Cu are integrated into a hybrid NIR‐II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH‐4T into the nanoparticle leads to 4.27‐fold fluorescence enhancement, resulting in brighter NIR‐II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR‐II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR‐II dye, detect tumors with NIR‐II/PET imaging, and guide intraoperative resection. The NIR‐II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image‐guided surgery.     

Nanoagents Based on Poly(ethylene glycol)‐b‐Poly(l‐thyroxine) Block Copolypeptide for Enhanced Dual‐Modality Imaging and Targeted Tumor Radiotherapy

Future healthcare requires development of novel theranostic agents that are capable of not only enhancing diagnosis and monitoring therapeutic responses but also augmenting therapeutic outcomes. Here, a versatile and stable nanoagent is reported based on poly(ethylene glycol)‐b‐poly(l ‐thyroxine) (PEG‐PThy) block copolypeptide for enhanced single photon emission computed tomography/computed tomography (SPECT/CT) dual‐modality imaging and targeted tumor radiotherapy in vivo. PEG‐PThy acquired by polymerization of l ‐thyroxine‐N‐carboxyanhydride (Thy‐NCA) displays a controlled M_n, high iodine content of ≈49.2 wt%, and can spontaneously form 65 nm‐sized nanoparticles (PThyN). In contrast to clinically used contrast agents like iohexol and iodixanol, PThyN reveals iso‐osmolality, low viscosity, and long circulation time. While PThyN exhibits comparable in vitro CT attenuation efficacy to iohexol, it greatly enhances in vivo CT imaging of vascular systems and soft tissues. PThyN allows for surface decoration with the cRGD peptide achieving enhanced CT imaging of subcutaneous B16F10 melanoma and orthotopic A549 lung tumor. Taking advantages of a facile iodine exchange reaction, ¹²⁵I‐labeled PThyN enables SPECT/CT imaging of tumors and monitoring of PThyN biodistribution in vivo. Besides, ¹³¹I‐labeled and cRGD‐functionalized PThyN displays remarkable growth inhibition of the B16F10 tumor in mice (tumor inhibition rate > 89%). These poly(l ‐thyroxine) nanoparticles provide a unique and versatile theranostic platform for varying diseases.     

Anti‐Biofouling Polymer‐Decorated Lutetium‐Based Nanoparticulate Contrast Agents for In Vivo High‐Resolution Trimodal Imaging

Nanomaterials have gained considerable attention and interest in the development of novel and high‐resolution contrast agents for medical diagnosis and prognosis in clinic. A classical urea‐based homogeneous precipitation route that combines the merits of in situ thermal decomposition and surface modification is introduced to construct polyethylene glycol molecule (PEG)‐decorated hybrid lutetium oxide nanoparticles (PEG–UCNPs). By utilizing the admirable optical and magnetic properties of the yielded PEG–UCNPs, in vivo up‐conversion luminescence and T₁‐enhanced magnetic resonance imaging of small animals are conducted, revealing obvious signals after subcutaneous and intravenous injection, respectively. Due to the strong X‐ray absorption and high atomic number of lanthanide elements, X‐ray computed‐tomography imaging based on PEG–UCNPs is then designed and carried out, achieving excellent imaging outcome in animal experiments. This is the first example of the usage of hybrid lutetium oxide nanoparticles as effective nanoprobes. Furthermore, biodistribution, clearance route, as well as long‐term toxicity are investigated in detail after intravenous injection in a murine model, indicating the overall safety of PEG–UCNPs. Compared with previous lanthanide fluorides, our nanoprobes exhibit more advantages, such as facile construction process and nearly total excretion from the animal body within a month. Taken together, these results promise the use of PEG–UCNPs as a safe and efficient nanoparticulate contrast agent for potential application in multimodal imaging.     

Functionalized NIR‐II Semiconducting Polymer Nanoparticles for Single‐cell to Whole‐Organ Imaging of PSMA‐Positive Prostate Cancer

Development of molecular probes holds great promise for early diagnosis of aggressive prostate cancer. Here, 2‐[3‐(1,3‐dicarboxypropyl) ureido] pentanedioic acid (DUPA)‐conjugated ligand and bis‐isoindigo‐based polymer (BTII) are synthesized to formulate semiconducting polymer nanoparticles (BTII‐DUPA SPN) as a prostate‐specific membrane antigen (PSMA)‐targeted probe for prostate cancer imaging in the NIR‐II window. Insights into the interaction of the imaging probes with the biological targets from single cell to whole organ are obtained by transient absorption (TA) microscopy and photoacoustic (PA) tomography. At single‐cell level, TA microscopy reveals the targeting efficiency, kinetics, and specificity of BTII‐DUPA SPN to PSMA‐positive prostate cancer. At organ level, PA tomographic imaging of BTII‐DUPA SPN in the NIR‐II window demonstrates superior imaging depth and contrast. By intravenous administration, BTII‐DUPA SPN demonstrates selective accumulation and retention in the PSMA‐positive tumor, allowing noninvasive PA detection of PSMA overexpressing prostate tumors in vivo. The distribution of nanoparticles inside the tumor tissue is further analyzed through TA microscopy. These results collectively demonstrate BTII‐DUPA SPN as a promising probe for prostate cancer diagnosis by PA tomography.     

Molecular Engineering of an Organic NIR‐II Fluorophore with Aggregation‐Induced Emission Characteristics for In Vivo Imaging

Design and synthesis of new fluorophores with emission in the second near‐infrared window (NIR‐II, 1000–1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR‐II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR‐II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR‐I aggregation‐induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal‐to‐background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image‐guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR‐II AIEgens and demonstrates the potential of NIR‐II AIEgens in vessel, lymphatic, and tumor imaging.     

Advanced Nanotechnology Leading the Way to Multimodal Imaging‐Guided Precision Surgical Therapy

Surgical resection is the primary and most effective treatment for most patients with solid tumors. However, patients suffer from postoperative recurrence and metastasis. In the past years, emerging nanotechnology has led the way to minimally invasive, precision and intelligent oncological surgery after the rapid development of minimally invasive surgical technology. Advanced nanotechnology in the construction of nanomaterials (NMs) for precision imaging‐guided surgery (IGS) as well as surgery‐assisted synergistic therapy is summarized, thereby unlocking the advantages of nanotechnology in multimodal IGS‐assisted precision synergistic cancer therapy. First, mechanisms and principles of NMs to surgical targets are briefly introduced. Multimodal imaging based on molecular imaging technologies provides a practical method to achieve intraoperative visualization with high resolution and deep tissue penetration. Moreover, multifunctional NMs synergize surgery with adjuvant therapy (e.g., chemotherapy, immunotherapy, phototherapy) to eliminate residual lesions. Finally, key issues in the development of ideal theranostic NMs associated with surgical applications and challenges of clinical transformation are discussed to push forward further development of NMs for multimodal IGS‐assisted precision synergistic cancer therapy.     

Low-Dose NIR-II Preclinical Bioimaging Using Liposome-Encapsulated Cyanine Dyes

Fluorescence imaging in the second near-infrared window (NIR-II, 1000–1700 nm) provides a powerful tool for in vivo structural and functional imaging in deep tissue. However, the lack of biocompatible contrast agents with bright NIR-II emission has hindered its application in fundamental research and clinical trials. Herein, a liposome encapsulation strategy for generating ultrabright liposome-cyanine dyes by restricting dyes in the hydrophobic pockets of lipids and inhibiting the aggregation, as corroborated by computational modeling, is reported. Compared with free indocyanine green (ICG, an US Food and Drug Administration-approved cyanine dye), liposome-encapsulated ICG (S-Lipo-ICG) shows a 38.7-fold increase in NIR-II brightness and enables cerebrovascular imaging at only one-tenth dose over a long period (30 min). By adjusting the excitation wavelength, two liposome-encapsulated cyanine dyes (S-Lipo-ICG and S-Lipo-FD1080) enable NIR-II dual-color imaging. Moreover, small tumor nodules (2–5 mm) can be successfully distinguished and removed with S-Lipo-ICG image-guided tumor surgery in rabbit models. This liposome encapsulation maintains the metabolic pathway of ICG, promising for clinical implementation.