Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

A reactive oxygen species (ROS)‐activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image‐guided ultrafast drug release and local‐regional therapy of the metastatic triple‐negative breast cancer (TNBC). RADV is prepared by integrating a ROS‐activatable Dox prodrug, a poly(ethylene glycol) (PEG)‐modified photosensitizer pyropheophorbide‐a, an unsaturated phospholipid 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self‐assembly of the phospholipid‐mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near‐infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local‐regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC.     

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple‐negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli‐responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme‐cleavable polyethylene glycol (PEG) corona, a light‐responsive photosensitizer pheophorbide a (PPa), and a temperature‐sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug‐loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa‐mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.     

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

O₂‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O₂‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O₂‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O₂‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.     

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.     

Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

A Near‐Infrared Light‐Triggered Nanocarrier with Reversible DNA Valves for Intracellular Controlled Release

A near‐infrared (NIR) light‐triggered nanocarrier is developed for intracellular controlled release with good stability, high nuclease resistance, and good biocompatibility. The nanocarrier consists of a gold nanorod core and mesoporous silica shell, capped with reversible single‐stranded DNA valves, which are manipulated by switching between the laser on/off states. Upon laser irradiation, the valves of the nanocarrier open and the cargo molecules can be released from the mesopores. When the NIR laser is turned off, the valves close and the nanocarrier stops releasing the cargo molecules. The release amount of the cargo molecules can be controlled precisely by adjusting the irradiation time and the laser on‐off cycles. Confocal fluorescence imaging shows that the nanocarrier can be triggered by the laser irradiation and the controlled release can be accomplished in living cells. Moreover, the therapeutic effect toward cancer cells can also be regulated when the chemotherapeutic drug doxorubicin is loaded into the nanocarrier. This novel approach provides an ideal platform for drug delivery by a NIR light‐activated mechanism with precise control of area, time, and especially dosage.     

Light-Controlled Nanosystem with Size-Flexibility Improves Targeted Retention for Tumor Suppression

Although great promise has been achieved with nanomedicines in cancer therapy, limitations are still encountered, such as short retention time in the tumor. Herein, a nanosystem that can modulate the particle size in situ by near-infrared (NIR) light is self-assembled by cross-linking the surface-modified poly(lactic-co-glycolic acid) from the up-conversion nanoparticle with indocyanine green and doxorubicin–nitrobenezene–polyethylene glycol (DOX–NB–PEG). The nanosystem with its small size (≈100 nm) achieves better tumor targeting, while the PEG on the surface of the nanosystem can effectively shield the adsorption of proteins during blood circulation, maintaining a stable nanostructure and achieving good tumor targeting. Moreover, the nanosystem at the tumor realizes the rapid shedding of PEG on its surface by NIR irradiation, and the enhanced cellular uptake. At the same time, aggregation occurs inside the nanosystem to form bigger particles (≈600 nm) in situ, prolonging the retention time at the tumor and producing enhanced targeted therapeutic effects. In vitro data show higher cellular uptake and a higher rate of apoptosis after irradiation, and the in vivo data prove that the nanosystem have a longer residence time at the tumor site after NIR irradiation. This nanosystem demonstrates an effective therapeutic strategy in targeted synergistic tumors.     

A Yolk–Shell Nanoplatform for Gene‐Silencing‐Enhanced Photolytic Ablation of Cancer

Noninvasive near‐infrared (NIR) light responsive therapy is a promising cancer treatment modality; however, some inherent drawbacks of conventional phototherapy heavily restrict its application in clinic. Rather than producing heat or reactive oxygen species in conventional NIR treatment, here a multifunctional yolk–shell nanoplatform is proposed that is able to generate microbubbles to destruct cancer cells upon NIR laser irradiation. Besides, the therapeutic effect is highly improved through the coalition of small interfering RNA (siRNA), which is codelivered by the nanoplatform. In vitro experiments demonstrate that siRNA significantly inhibits expression of protective proteins and reduces the tolerance of cancer cells to bubble‐induced environmental damage. In this way, higher cytotoxicity is achieved by utilizing the yolk–shell nanoparticles than treated with the same nanoparticles missing siRNA under NIR laser irradiation. After surface modification with polyethylene glycol and transferrin, the yolk–shell nanoparticles can target tumors selectively, as demonstrated from the photoacoustic and ultrasonic imaging in vivo. The yolk–shell nanoplatform shows outstanding tumor regression with minimal side effects under NIR laser irradiation. Therefore, the multifunctional nanoparticles that combining bubble‐induced mechanical effect with RNA interference are expected to be an effective NIR light responsive oncotherapy.     

Near‐Infrared Laser‐Triggered Nitric Oxide Nanogenerators for the Reversal of Multidrug Resistance in Cancer

The potential therapeutic implications of nitric oxide (NO) for diverse diseases have been under consideration for years; however, the development of precisely controllable NO generation system with potential for clinical application has remained elusive. Herein, intelligent near‐infrared (NIR) laser‐triggered NO nanogenerators for the treatment of multidrug‐resistant (MDR) cancer are fabricated by integrating photothermal agents and heat‐sensitive NO donors into a single nanoparticle. Such nanogenerators can absorb 808 nm NIR photons and convert them into ample heat to trigger NO release. The generated NO molecules are demonstrated to successfully achieve multidrug‐resistance reversal by inhibiting the expression of P‐glycol protein. Consequently, the intracellular accumulation of doxorubicin is effectively increased, resulting in high toxicity to MDR cancer cells in vitro. By virtue of surface modification with targeting ligands, these nanoparticles are able to selectively accumulate in tumor tissue. The therapeutic effects of the nanogenerators are validated in a humanized MDR cancer model. The in vivo experiment indicates that the nanoparticles possess excellent tumor suppression functionality with few side effects upon NIR laser exposure. Therefore, this novel photothermal conversion‐based NO‐releasing platform is expected to be a potential alternative to clinical MDR cancer treatment and may provide insights with regard to other NO‐relevant medical treatments.     

Gold Nanoshell Nanomicelles for Potential Magnetic Resonance Imaging,Light‐Triggered Drug Release,and Photothermal Therapy

A novel multifunctional drug‐delivery platform is developed based on cholesteryl succinyl silane (CSS) nanomicelles loaded with doxorubicin, Fe₃O₄ magnetic nanoparticles, and gold nanoshells (CDF‐Au‐shell nanomicelles) to combine magnetic resonance (MR) imaging, magnetic‐targeted drug delivery, light‐triggered drug release, and photothermal therapy. The nanomicelles show improved drug‐encapsulation efficiency and loading level, and a good response to magnetic fields, even after the formation of the gold nanoshell. An enhancement for T₂‐weighted MR imaging is observed for the CDF‐Au‐shell nanomicelles. These nanomicelles display surface plasmon absorbance in the near‐infrared (NIR) region, thus exhibiting an NIR (808 nm)‐induced temperature elevation and an NIR light‐triggered and stepwise release behavior of doxorubicin due to the unique characteristics of the CSS nanomicelles. Photothermal cytotoxicity in vitro confirms that the CDF‐Au‐shell nanomicelles cause cell death through photothermal effects only under NIR laser irradiation. Cancer cells incubated with CDF‐Au‐shell nanomicelles show a significant decrease in cell viability only in the presence of both NIR irradiation and a magnetic field, which is attributed to the synergetic effects of the magnetic‐field‐guided drug delivery and the photothermal therapy. Therefore, such multicomponent nanomicelles can be developed as a smart and promising nanosystem that integrates multiple capabilities for effective cancer diagnosis and therapy.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

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.     

Covalent Organic Framework‐Supported Molecularly Dispersed Near‐Infrared Dyes Boost Immunogenic Phototherapy against Tumors

Photodynamic therapy (PDT) mediated by near‐infrared (NIR) dyes is a promising cancer treatment modality; however, its use is limited by significant challenges, such as hypoxic tumor microenvironments and self‐quenching of photosensitizers. These challenges hamper its utility in inducing immunogenic cell death (ICD) and triggering potent systemic antitumor immune responses. This study demonstrates that molecular dispersion of NIR dyes in nanocarriers can significantly enhance their ability to produce reactive oxygen species and potentiate synergistic PDT and photothermal therapy against tumors. Specifically, NIR dye indocyanine green (ICG) can be spontaneously adsorbed to covalent organic frameworks (COFs) via π–π conjugations to prevent intermolecular stacking interactions. Then, ICG‐loaded COFs are ultrasonically exfoliated and coated with polydopamine (PDA) to construct a new phototherapeutic agent ICG@COF‐1@PDA with enhanced efficacy. In conjunction with ICG@COF‐1@PDA, a single round of NIR laser irradiation can induce obvious ICD, elicit antitumor immunity in colorectal cancer, and yield 62.9% inhibition of untreated distant tumors. ICG@COF‐1@PDA also exhibits notable phototherapeutic efficacy against 4T1 murine breast to lung metastasis, a spontaneous metastasis mode for triple‐negative breast cancers (TNBCs). Overall, this study reveals a novel nanodelivery system for molecular dispersion of NIR dyes, which may present new therapeutic opportunities against primary and metastatic tumors.     

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.     

Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

Photoresponsive Protein–Graphene–Protein Hybrid Capsules with Dual Targeted Heat‐Triggered Drug Delivery Approach for Enhanced Tumor Therapy

A novel photo‐responsive protein–graphene–protein (PGP) capsule that doubles as a photothermal agent with core/shell structure is constructed by anchoring reduced graphene oxide nanosheets on one‐component protein (lactoferrin) shell through a double emulsion method. PGP capsules can transport fully concealed hydrophilic anticancer cargo, doxorubicin (Dox), with a large payload (9.43 μmol g^‐1) to be later unloaded in a burst‐like manner by photo‐actuation triggered by near‐infrared irradiation. Being biocompatible yet with a high cancer cell targeting efficiency, PGP capsules have successfully eradicated subcutaneous tumors in 10 d following a single 5 min NIR irradiation without distal damage. Besides, the photochemothermal therapy of PGP capsules eradicates tumor cells not only in the light‐treating area but also widely light‐omitted tumor cells, overcoming the tumor recurrence due to efficient cell killing efficacy. These results demonstrate that the PGP capsule is a potential new drug delivery platform for local‐targeting, on‐demand, photoresponsive, combined chemotherapy/hyperthermia for tumor treatment and other biomedical applications.     

Bismuth Ferrite‐Based Nanoplatform Design: An Ablation Mechanism Study of Solid Tumor and NIR‐Triggered Photothermal/Photodynamic Combination Cancer Therapy

Although nanomaterial‐mediated phototherapy, in particular photothermal therapy (PTT) and photodynamic therapy (PDT), is extensively investigated in recent years, the ablation mechanism, evolution, and rehabilitation process of in vivo solid tumor after phototherapy are rarely explored yet and remain a terra incognita. Herein, a kind of bismuth ferrite nanoparticles (abbreviated as BFO NPs) are strategically designed and synthesized with a desirable size and bioactivity as a brand‐new phototherapeutic agent for the phototherapy, which are of strong near infrared (NIR) absorbance, excellent biocompatibility, and outstanding photophysical activity for the hyperthemia and reactive oxygen species generation. Resultantly, BFO NPs can realize simultaneous PTT/PDT synergistic therapy outcome against cancer cells and solid tumor under NIR laser irradiation. Meanwhile, for the first time, more attentions are paid to demonstrate ablation mechanism and evolution process of in vivo solid tumor after phototherapy by B‐mode ultrasonography/magnetic resonance imaging as well as histopathological analysis, all of which verify a series of physiological processes, being in order of necrosis of parenchymal cells, in situ tissue disintegration, liquefaction, and finally encapsulation process.     

Tumor Microenvironment Activated Photothermal Strategy for Precisely Controlled Ablation of Solid Tumors upon NIR Irradiation

Photothermal ablation has provided emerging and promising opportunities to further potentiate the efficacy of postoperative chemotherapy of tumor. However, it still cannot achieve a high level of selectivity because extraneous photodamage along the optical path to the tumor is unavoidable as the result of the uncontrollable distribution of the photothermal agents. In addition, it is technically difficult to keep photoirradiation localizing only on cancer cells. In this report, a new strategy is introduced for precisely controlled ablation of tumor through tumor microenvironment activated near‐infrared (NIR) photothermal therapy. By taking advantage of the pH‐dependent light‐heat conversion property of Au@PANI nanoparticles, much higher photothermal effect at pH 6.5 than that at pH 7.4 is achieved. Therefore, in normal tissues and blood vessels, NIR irradiation cannot lead to a lethal temperature with little or no harm to normal cells. In contrast, in acidic tumor microenvironment, the photothermal effect is activated. Consequently, NIR irradiation can effectively kill cancer cells through local hyperthermia. Importantly, with the benefit of the internal and external control to switch on the photothermal ablation, the technical difficulty to precisely localize laser irradiation on tumor cells can be circumvented.     

NIR‐Activated Supersensitive Drug Release Using Nanoparticles with a Flow Core

Near infrared (NIR) light‐activated supersensitive drug release via photothermal conversion is of particular interest due to its advantages in spatial and temporal control. However, such supersensitive drug release is rarely reported for polymeric nanoparticles. In this study, polymeric nanoparticles observed with flowable core can achieve NIR‐activated supersensitive drug release under the assistance of photothermal agent. It is demonstrated that only 5 s NIR irradiation (808 nm, 0.3 W cm^?2) leads to 17.8% of doxorubicin (DOX) release, while its release is almost completely stopped when the NIR laser is switched off. In contrast, the control, poly(d ,l ‐lactide) nanoparticles with rigid cores, do not exhibit such supersensitive effect. It is demonstrated that intraparticle temperature is notably increased during photothermal conversion by detecting fluorescein lifetime using a time‐correlated single photon counting (TCSPC) technique, which is the main driving force for such supersensitive drug release from hydrophobic flow core. In contrast, rigid chain of nanoparticular core hinders drug diffusion. Furthermore, such NIR light‐activated supersensitive drug release is demonstrated, which significantly enhances its anticancer efficacy, resulting in overcoming of the resistance of cancer cells against DOX treatment in vitro and in vivo. This simple and highly universal strategy provides a new approach to fabricate NIR light‐activated supersensitive drug delivery systems.