All‐in‐One Phototheranostics: Single Laser Triggers NIR‐II Fluorescence/Photoacoustic Imaging Guided Photothermal/Photodynamic/Chemo Combination Therapy

Development of single near‐infrared (NIR) laser triggered phototheranostics for multimodal imaging guided combination therapy is highly desirable but is still a big challenge. Herein, a novel small‐molecule dye DPP‐BT is designed and synthesized, which shows strong absorption in the first NIR window (NIR‐I) and fluorescence emission in the second NIR region (NIR‐II). Such a dye not only acts as a dual‐modal contrast agent for NIR‐II fluorescence and photoacoustic (PA) imaging, but also serves as a combined therapeutic agent for photothermal therapy (PTT) and photodynamic therapy (PDT). The single NIR laser triggered all‐in‐one phototheranostic nanoparticles are constructed by encapsulating the dye DPP‐BT, chemotherapy drug DOX, and natural phase‐change materials with a folic acid functionalized amphiphile. Notably, under NIR laser irradiation, DOX can effectively release from such nanoparticles via NIR‐induced hyperthermia of DPP‐BT. By intravenous injection of such nanoparticles into Hela tumor‐bearing mice, the tumor size and location can be accurately observed via NIR‐II fluorescence/PA dual‐modal imaging. From in vitro and in vivo therapy results, such nanoparticles simultaneously present remarkable antitumor efficacy by PTT/PDT/chemo combination therapy, which is triggered by a single NIR laser. Overall, this work provides an innovative strategy to design and construct all‐in‐one nanoplatforms for clinical phototheranostics.     

Two‐Stage Size Decrease and Enhanced Photoacoustic Performance of Stimuli‐Responsive Polymer‐Gold Nanorod Assembly for Increased Tumor Penetration

A promising theranostic platform for solid tumors would deliver and release anticancer nanomedicine effectively in tumor cells. However, diverse biological barriers, especially related to the tumor microenvironment, impede these theranostic agents from reaching the tumor cell. Herein, a sequential pH and reduction‐responsive polymer and gold nanorod (AuNR) core–shell assembly to overcome these barriers via a two‐stage size decrease and disassembly of the nanoplatform responding to the specified tumor microenvironment are reported. The tumor uptake of the hybrid nanoparticle (NP) is 14.2% ID g^?1, which is two and four times higher than the noneresponsive hybrid NPs and small AuNR@PEG, respectively. After tumor uptake of the hybrid NPs, the disassembled ultrasmall AuNRs coated with a polymer of polymerized reduction‐responsive doxorubicin (DOX) prodrug monomers penetrate into the solid tumor and lead to localized DOX release in the tumor cell. A linear increase in photoacustic (PA) effects from the PA activating polymer on an AuNR cluster surface indicates a critical role of electromagnetic fields in the AuNR assembly, which is consistent with the theoretical calculation results. Furthermore, the hybrid NP can serve as a promising deep‐tissue PA and surface‐enhanced Raman scattering imaging agent for real‐time in vivo investigation of physiological behaviors and deep tumor penetrating nanotherapy effects.     

Mesoporous Silica Coated Single‐Walled Carbon Nanotubes as a Multifunctional Light‐Responsive Platform for Cancer Combination Therapy

The development of cancer combination therapies, many of which rely on nanoscale theranostic agents, has received increasing attention in recent years. In this work, polyethylene glycol (PEG) modified mesoporous silica (MS) coated single‐walled carbon nanotubes (SWNTs) are fabricated and utilized as a multifunctional platform for imaging guided combination therapy of cancer. A model chemotherapy drug, doxorubicin (DOX), could be loaded into the mesoporous structure of the obtained SWNT@MS‐PEG nano‐carriers with high efficiency. Upon stimulation under near‐infrared (NIR) light, photothermally triggered drug release from DOX loaded SWNT@MS‐PEG is observed inside cells, resulting in a synergistic cancer cell killing effect. As revealed by both photoacoustic (PA) and magnetic resonance (MR) imaging, we further uncover efficient tumor accumulation of SWNT@MS‐PEG/DOX after intravenous injection into mice. In vivo combination therapy using this agent is further demonstrated in a mouse tumor model, achieving a remarkable synergistic anti‐tumor effect superior to that obtained by mono‐therapy. Our work presents a new type of theranostic nano‐platform, which could load therapeutic molecules with high efficiency, be responsive to external NIR stimulation, and at the same time serve as a diagnostic imaging agent.     

Redox Sensitive Hyaluronic Acid‐Decorated Graphene Oxide for Photothermally Controlled Tumor‐Cytoplasm‐Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox‐sensitive, hyaluronic acid‐decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm‐specific rapid delivery using near‐infrared (NIR) irradiation controlled endo/lysosome disruption and redox‐triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox‐sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug‐loading capacity for aromatic molecules, HA receptor‐mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox‐dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA‐receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm‐specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox‐triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.     

SnTe@MnO2‐SP Nanosheet–Based Intelligent Nanoplatform for Second Near‐Infrared Light–Mediated Cancer Theranostics

Near infrared light, especially the second near‐infrared light (NIR II) biowindows with deep penetration and high sensitivity are widely used for optical diagnosis and phototherapy. Here, a novel kind of 2D SnTe@MnO₂‐SP nanosheet (NS)‐based nanoplatform is developed for cancer theranostics with NIR II‐mediated precise optical imaging and effective photothermal ablation of mouse xenografted tumors. The 2D SnTe@MnO₂‐SP NSs are fabricated via a facile method combining ball‐milling and liquid exfoliation for synthesis of SnTe NSs, and surface coating MnO₂ shell and soybean phospholipid (SP). The ultrathin SnTe@MnO₂‐SP NSs reveal notably high photothermal conversion efficiency (38.2% in NIR I and 43.9% in NIR II). The SnTe@MnO₂‐SP NSs inherently feature tumor microenvironment (TME)‐responsive biodegradability, and the main metabolite TeO₃^2? shows great antitumor effect, coupling synergetic chemotherapy for cancer. Moreover, the SnTe@MnO₂‐SP NSs also exhibit great potential for fluorescence, photoacoustic (PA), and photothermal imaging agents in the NIR II biowindow with much higher resolution and sensitivity. This is the first report, as far as is known, with such an inorganic nanoagent setting fluorescence/PA/photothermal imaging and photothermal therapy in NIR II biowindow and TME‐responsive biodegradability rolled into one, which provide insight into the clinical potential for cancer theranostics.     

Ultrasmall Semiconducting Polymer Dots with Rapid Clearance for Second Near‐Infrared Photoacoustic Imaging and Photothermal Cancer Therapy

Phototheranostic agents in the second near‐infrared (NIR‐II) window (1000–1700 nm) are emerging as a promising theranostic platform for precision medicine due to enhanced penetration depth and minimized tissue exposure. The development of metabolizable NIR‐II nanoagents for imaging‐guided therapy are essential for noninvasive disease diagnosis and precise ablation of tumors. Herein, metabolizable highly absorbing NIR‐II conjugated polymer dots (Pdots) are reported for the first time for photoacoustic imaging guided photothermal therapy (PTT). The unique design of low‐bandgap D‐A π‐conjugated polymer (DPP‐BTzTD) together with modified nanoreprecipitation conditions allows to fabricate NIR‐II absorbing Pdots with ultrasmall (4 nm) particle size. Extensive experimental tests demonstrate that the constructed Pdots exhibit good biocompatibility, excellent photostability, bright photoacoustic signals, and high photothermal conversion efficiency (53%). In addition, upon tail‐vein intravenous injection of tumor‐bearing mice, Pdots also show high‐efficient tumor ablation capability with rapid excretion from the body. In particular, both in vitro and in vivo assays indicate that the Pdots possess remarkable PTT performance under irradiation with a 1064 nm laser with 0.5 W cm^?2, which is much lower than its maximum permissible exposure limit of 1 W cm^?2. This pilot study thus paves a novel avenue for the development of organic semiconducting nanoagents for future clinical translation.     

pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.     

Fast and Accurate Imaging of Lymph Node Metastasis with Multifunctional Near‐Infrared Polymer Dots

Metastasis to regional lymph nodes is a significant prognostic indicator for cancer progression. There is a great demand for rapid and accurate diagnosis of metastasis to the lymph nodes. In this work, folate receptor‐targeted trimodal polymer dots are designed for near‐infrared (NIR)/photoacoustic (PA)/magnetic resonance (MR) imaging of lymph node metastasis. Confocal microscopic analyses and flow cytometry show that pulmonary mucosa epithelial cell carcinoma NCI‐H292 with expression of the folate receptor is positive for folate‐functional polymer dots. In vivo and ex vivo NIR imaging results verify that prepared polymer dots show rapid and high uptake in the metastatic lymph nodes, can effectively distinguish metastatic and normal lymph nodes for 1 h postinjection, and have great potential in real‐time imaging‐guided surgery. Furthermore, ten metastatic lymph nodes from the tumor‐bearing mice are detected by NIR imaging via intratumoral injection of polymer dots. Moreover, in vivo PA and MR imaging confirm the enhanced PA and MR signals of polymer dots in the metastatic lymph nodes as well as enlarged lymph nodes in tumor‐bearing mice. The results of this study provide a unique approach using trimodal polymer dots for the rapid and precise diagnosis of lymph node metastasis in vivo.     

NIR Light‐Triggered Degradable MoTe2 Nanosheets for Combined Photothermal and Chemotherapy of Cancer

Telluride molybdenum (MoTe₂) nanosheets with wide near‐infrared (NIR) absorbance are functionalized with polyethylene glycol‐cyclic arginine‐glycine‐aspartic acid tripeptide (PEG‐cRGD). After loading a chemotherapeutic drug (doxorubicin, DOX), MoTe₂‐PEG‐cRGD/DOX is used for combined photothermal therapy and chemotherapy. With the high photothermal conversion efficiency, MoTe₂‐PEG‐cRGD/DOX exhibits favorable cells killing ability under NIR irradiation. Owing to the cRGD‐mediated specific tumor targeting, MoTe₂‐PEG‐cRGD/DOX shows efficient accumulation in tumors to induce a strong tumor ablation effect. MoTe₂‐PEG‐cRGD nanosheets, which are relatively stable in the circulation, could be degraded under NIR ray. The in vitro and in vivo experimental results demonstrate that this theranostic nanoagent, which could accumulate in tumors to allow photothermal imaging and combined therapy, is readily degradable in normal organs to enable rapid excretion and avoid long‐term retention/toxicity, holding great potential to treat tumor effectively.     

Design and Synthesis of “All‐in‐One” Multifunctional FeS2 Nanoparticles for Magnetic Resonance and Near‐Infrared Imaging Guided Photothermal Therapy of Tumors

The ideal theranostic nanoplatform for tumors is a single nanoparticle that has a single semiconductor or metal component and contains all multimodel imaging and therapy abilities. The design and preparation of such a nanoparticle remains a serious challenge. Here, with FeS₂ as a model of a semiconductor, the tuning of vacancy concentrations for obtaining “all‐in‐one” type FeS₂ nanoparticles is reported. FeS₂ nanoparticles with size of ≈30 nm have decreased photoabsorption intensity from the visible to near‐infrared (NIR) region, due to a low S vacancy concentration. By tuning their shape/size and then enhancing the S vacancy concentration, the photoabsorption intensity of FeS₂ nanoparticles with size of ≈350 nm (FeS₂‐350) goes up with the increase of the wavelength from 550 to 950 nm, conferring the high NIR photothermal effect for thermal imaging. Furthermore, this nanoparticle has excellent magnetic properties for T₂‐weighted magnetic resonance imaging (MRI). Subsequently, FeS₂‐350 phosphate buffer saline (PBS) dispersion is injected into the tumor‐bearing mice. Under the irradiation of 915‐nm laser, the tumor can be ablated and the metastasis lesions in liver suffer significant inhibition. Therefore, FeS₂‐350 has great potential to be used as novel “all‐in‐one” multifunctional theranostic nanoagents for MRI and NIR dual‐modal imaging guided NIR‐photothermal ablation therapy (PAT) of tumors.     

Multifunctional Biomedical Imaging in Physiological and Pathological Conditions Using a NIR‐II Probe

Compared with imaging in the visible (400–650 nm) and near‐infrared window I (NIR‐I, 650–900 nm) regions, imaging in near‐infrared window II (NIR‐II, 1000–1700 nm) is a highly promising in vivo imaging modality with improved resolution and deeper tissue penetration. Here, a small molecule NIR‐II dye,5,5′‐(1H,5H‐benzo[1,2‐c:4,5‐c′] bis[1,2,5]thiadiazole)‐4,8‐diyl)bis(N,N‐bis(4‐(3‐((tert‐butyldimethylsilyl)oxy)propyl)phenyl) thiophen‐2‐amine), is successfully encapsulated into phospholipid vesicles to prepare a probe CQS1000. The novel NIR‐II probe is studied for in vivo multifunctional biological imaging. The results of this study indicate that the NIR‐II vesicle CQS1000 can noninvasively and dynamically visualize and monitor many physiological and pathological conditions of circulatory systems, including lymphatic drainage and routing, angiogenesis of tumor, and vascular deformity such as arterial thrombus formation and ischemia with high spatial and temporal resolution. More importantly, by virtue of the favorable half‐life of blood circulation of CQS1000, NIR‐II imaging is capable of aiding precise resection of tumor such as osteosarcoma and accelerating the process of lymph node dissection to complete sentinel lymph node biopsy for better decision making during the tumor surgery. Overall, CQS1000 is a highly promising NIR‐II probe for multifunctional biomedical imaging in physiological and pathological conditions, surpassing traditional NIR‐I imaging modality and pathologic assessments for clinical diagnosis and treatment.     

Monitoring the Real‐Time Circulatory System‐Related Physiological and Pathological Processes In Vivo Using a Multifunctional NIR‐II Probe

The dysfunction of the circulatory system leads to various pathological processes with high morbidity. Recently, fluorescence imaging in the near‐infrared II (NIR‐II) window (1000–1700 nm) has attracted immense attention in many biological processes. The rapid metabolism and low toxicity of some NIR‐II organic small molecules indicate their feasibility for use in visualizing the circulatory system. However, most of the reported NIR‐II organic small molecules presently encounter such dilemmas as complicated synthetic procedures and low quantum yields (QY). To address this challenge, a series of facilely prepared NIR‐II organic small molecule CQ‐T (CQ‐1‐4T) are designed and these compounds are loaded with biocompatible human serum albumin (HSA) to improve QY. Among them, CQL (CQ‐4T/HSA) demonstrates superior optical properties and a 6.65‐fold increase in fluorescence compared to the small molecule alone. Further work validates the efficacy and accuracy of CQL in monitoring the real‐time circulatory system‐related physiological and pathological processes in vivo, including thrombosis, peripheral arterial disease, tumor angiogenesis, and lymphatic drainage. Moreover, the excellent optical properties of CQL enable precise tumor resection and sentinel lymph node biopsy under NIR‐II navigation. In conclusion, CQL is a novel and promising NIR‐II organic probe with multifunctional imaging capability. It is highly desirable to accelerate its future translations into the clinic.     

Photo‐ and pH‐Triggered Release of Anticancer Drugs from Mesoporous Silica‐Coated Pd@Ag Nanoparticles

A smart drug delivery system integrating both photothermal therapy and chemotherapy for killing cancer cells is reported. The delivery system is based on a mesoporous silica‐coated Pd@Ag nanoplates composite. The Pd@Ag nanoplate core can effectively absorb and convert near infrared (NIR) light into heat. The mesoporous silica shell is provided as the host for loading anticancer drug, doxorubicin (DOX). The mesoporous shell consists of large pores, ～10 nm in diameter, and allows the DOX loading as high as 49% in weight. DOX loaded core–shell nanoparticles exhibit a higher efficiency in killing cancer cells than free DOX. More importantly, DOX molecules are loaded in the mesopores shell through coordination bonds that are responsive to pH and heat. The release of DOX from the core‐shell delivery vehicles into cancer cells can be therefore triggered by the pH drop caused by endocytosis and also NIR irradiation. A synergistic effect of combining chemotherapy and photothermal therapy is observed in our core‐shell drug delivery system. The cell‐killing efficacy by DOX‐loaded core–shell particles under NIR irradiation is higher than the sum of chemotherapy by DOX‐loaded particles and photothermal therapy by core–shell particles without DOX.     

Self‐Assembly of Semiconducting Polymer Amphiphiles for In Vivo Photoacoustic Imaging

Despite the advantages of semiconducting polymer nanoparticles (SPNs) over other inorganic nanoparticles for photoacoustic (PA) imaging, their synthetic method is generally limited to nanoprecipitation, which is likely to cause the issue of nanoparticle dissociation. The synthesis of near‐infrared (NIR) absorbing semiconducting polymer amphiphiles (SPAs) that can spontaneously self‐assemble into homogeneous nanoparticles for in vivo PA imaging is reported. As compared with their counterpart nanoparticles (SPN1) prepared through nanoprecipitation, SPAs generally have higher fluorescence quantum yields but similar size and PA brightness, making them superior over SPN1. Optical and simulation studies reveal that the poly(ethylene glycol) (PEG) grafting density plays a critical role in determining the packing of SP segments inside the core of nanoparticles, consequently affecting the optical properties. The small size and structurally stable nanostructure, in conjunction with a dense PEG shell, allow SPAs to passively target tumors of living mice after systemic administration, permitting both PA and fluorescence imaging of the tumors at signals that are ≈1.5‐fold higher than that of liver. This study thus not only provides the first generation of amphiphilic optically active polymers for PA imaging, but also highlights the molecular guidelines for the development of organic NIR imaging nanomaterials.     

Multi‐Caged IrOx for Facile Preparation of “Six‐in‐One” Nanoagent for Subcutaneous and Lymphatic Tumors Inhibition against Recurrence and Metastasis

Single nanocarriers with intrinsic characteristics of diagnosis, effective therapy against solid malignancies with fatal metastasis, and tumor microenvironment regulation are promising in construction of a simple and effective multimode nanotheranostic system. Herein, multi‐caged IrO_x nanocarriers are fabricated by direct thermal hydrolysis strategy, which exhibit good sono‐photodynamic response, outstanding gemstone spectral computed tomography, and photoacoustic (PA) imaging capabilities, universal loading, and pinpoint drug release properties. As a proof of concept, a gemstone spectral computed tomography/PA/fluorescence imaging–guided oxygen self‐sufficient sono‐photo‐chemotherapy nanoagent by simple loading of doxorubicin is constructed. The remarkable synergistic therapy and excellent hypoxia releasing capabilities can remove both subcutaneous and sentinel lymph nodes metastasis tumors, and effectively suppress tumor recurrence and lung metastasis, thus greatly prolonging survival time. The study provides an attractive candidate to construct a “six‐in‐one” (tri‐modal therapies and three imaging modalities) tumor theranostic system.     

Smart Ferrofluid with Quick Gel Transformation in Tumors for MRI‐Guided Local Magnetic Thermochemotherapy

Improved techniques for local administration of anticancer drugs are needed to reduce the side effects of chemotherapy owing to leakage of anticancer drugs from tumors and to enhance therapeutic efficacy. This study presents the development of smart ferrofluid that transforms immediately into a gel in tumors and generates heat in response to an alternating magnetic field (AMF), simultaneously releasing the anticancer drug. The smart ferrofluid, which is synthesized using less toxic magnetic materials (Fe₃O₄ nanoparticles), natural polysaccharides (alginate), and amino acids (cysteine), can also act as a contrast agent for magnetic resonance imaging (MRI). The ferrofluid also incorporates an anticancer drug (i.e., doxorubicin, DOX) via hydrogen bonds. AMF causes heating of gels prepared from the DOX‐containing ferrofluid, resulting in gel shrinkage and DOX release. In vivo experiments demonstrated that the ferrofluid transforms into a gel in the tumor, with the gel remaining in the tumor. Furthermore, magnetic thermochemotherapy using this ferrofluid inhibited tumor growth, while magnetic hyperthermia alone had only a marginal effect. Thus, the combination of magnetic hyperthermia and chemotherapy may be important for suppressing tumor growth. In summary, the ferrofluid presented here has the potential to facilitate MRI‐guided magnetic thermochemotherapy through a combination of endoscopic technologies in the future.     

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging‐Guided Combinatorial Chemo‐Photothermal Therapy

Near‐infrared (NIR)‐absorbing metal‐based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal‐controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta‐derived nanomaterials represent promising candidates for biomedical applications. However, Ta‐based nanomaterials by themselves have not been explored for NIR‐mediated photothermal ablation therapy. In this work, an innovative Ta‐based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS₂) nanosheets (NSs) is reported for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS₂ NSs exhibit multiple unique features including (i) efficient NIR light‐to‐heat conversion with a high photothermal conversion efficiency of 39%, (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat‐enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. It is expected that this multifunctional NS platform can serve as a promising candidate for imaging‐guided cancer therapy and selection of cancer patients with high tumor accumulation.     

Surface State Mediated NIR Two‐Photon Fluorescence of Iron Oxides for Nonlinear Optical Microscopy

The development of fluorescent iron oxide nanomaterials is highly desired for multimodal molecular imaging. Instead of incorporating fluorescent dyes on the surface of iron oxides, a ligand‐assisted synthesis approach is developed to allow near‐infrared (NIR) fluorescence in Fe₃O₄ nanostructures. Using a trimesic acid (TMA)/citrate‐mediated synthesis, fabricated Fe₃O₄ nanostructures can generate a NIR two‐photon florescence (TPF) peak around 700 nm under the excitation by a 1230‐nm femtosecond laser. By tailoring the absorption of Fe₃O₄ nanostructures toward NIR band, the NIR‐TPF efficiency can be greatly increased. Through internal etching, surface peeling, and ligand replacement, spectroscopic results validated that such resonantly enhanced NIR‐TPF is mediated by surface states with strong NIR‐IR absorption. This TPF signal evolution can be generalized to other iron oxide nanomaterials like magnetite nanoparticles and α‐Fe₂O₃ nanoplates. Using the developed fluorescent Fe₃O₄ nanostructures, it is demonstrated that their TPF and third harmonic generation (THG) contrast in the nonlinear optical microscopy of live cells. It is anticipated that the synthesized NIR photofunctional Fe₃O₄ will serve as a versatile platform for dual‐modality magnetic resonance imaging (MRI) as well as a magnet‐guided theranostic agent.     

Unprecedented “All‐in‐One” Lanthanide‐Doped Mesoporous Silica Frameworks for Fluorescence/MR Imaging and Combination of NIR Light Triggered Chemo‐Photodynamic Therapy of Tumors

Designing a single multifunctional nanoparticle that can simultaneously impart both diagnostic and therapeutic functions is considered to be a long‐lasting hurdle for biomedical researchers. Conventionally, a multifunctional nanoparticle can be constructed by integrating organic dyes/magnetic nanoparticles to impart diagnostic functions and anticancer drugs/photosensitizers to achieve therapeutic outcomes. These multicomponents systems usually suffer from severe photobleaching problems and cannot be activated by near‐infrared (NIR) light. Here, it is demonstrated that all‐in‐one lanthanide‐doped mesoporous silica frameworks (EuGdOx@MSF) loaded with an anticancer drug, doxorubicin (DOX) can facilitate simultaneous bimodal magnetic resonance (MR) imaging with approximately twofold higher T₁‐MR contrast as compared to the commercial Gd(III)‐DTPA complex and fluorescence imaging with excellent photostability. Upon a very low dose (130 mW cm^?2) of NIR light (980 nm) irradiation, the EuGdOx@MSF not only can sensitize formation of singlet oxygen (¹O₂) by itself but also can phototrigger the release of the DOX payload effectively to exert combined chemo‐photodynamic therapeutic (PDT) effects and destroy solid tumors in mice completely. It is also discovered for the first time that the EuGdOx@MSF‐mediated PDT effect can suppress the level of the key drug resistant protein, i.e., p‐glycoprotein (p‐gp) and help alleviate the drug resistant problem commonly associated with many cancers.     

Enhanced Nanodrug Delivery to Solid Tumors Based on a Tumor Vasculature‐Targeted Strategy

Tumor angiogenesis is a hallmark of tumor growth and metastasis, and inhibition of tumor angiogenesis is an effective strategy for tumor therapy. The high expression levels of specific biomarkers such as integrin receptors (e.g., α_vβ₃) in the endothelium of tumor vessels make angiogenesis an ideal target for drug delivery and thus tumor therapy. Herein, a new nanodrug (T&D@RGD‐Ag₂S) is presented, which can effectively inhibit tumor growth by integrating the specific recognition peptide cyclo(Arg‐Gly‐Asp‐d‐Phe‐Cys) (cRGD) for tumor vascular targeting, the broad‐spectrum endothelial inhibitor O‐(chloroacetyl‐carbamoyl) fumagillol (TNP‐470), and chemotherapeutic drug doxorubicin (DOX) for synergetic tumor therapy. The results show that the T&D@RGD‐Ag₂S nanodrug rapidly and specifically binds to the tumor vasculature after intravenous injection. Tumor vascular density is greatly reduced following effective angiogenesis inhibition by TNP‐470. Meanwhile, increased delivery of DOX deep into the tumor induces extensive tumor apoptosis, resulting in remarkable tumor growth inhibition in a human U87‐MG malignant glioma xenograft model. In addition, the therapeutic effects of T&D@RGD‐Ag₂S on inhibiting tumor growth and decreasing vessel density are monitored in situ using near‐infrared II (NIR‐II) fluorescence imaging of Ag₂S quantum dots. This tumor vasculature‐targeted strategy can be extended as a general method for treating a broad range of tumors and holds promise for future clinical applications.