Engineering Versatile Nanoparticles for Near‐Infrared Light‐Tunable Drug Release and Photothermal Degradation of Amyloid β

Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off‐target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ‐binding affinity, stimuli‐responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near‐infrared (NIR)‐absorbing conjugated polymer PDPP3T‐O14 serves as a photothermal core while thermal‐responsive polymer 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine at the outer layer as the NIR‐stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5‐mer β‐sheet breaker peptides LPFFD (Leu‐Pro‐Phe‐Phe‐Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol‐lipid shell for active Aβ‐targeting. The resultant NPs exhibit good Aβ‐targeting ability and obvious photothermal dissociation effect together with Aβ aggregation‐dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti‐amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ‐induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.     

Protease-Activatable Nanozyme with Photoacoustic and Tumor-Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy

Despite the promise of ferrotherapy in cancer treatment, current ferrous therapeutics suffer from compromised antitumor ferroptosis efficacy and low specificity for tumors. Herein, a protease-activatable nanozyme (Fe₃O₄@Cu_1.77Se) is reported for photoacoustic and tumor-enhanced magnetic resonance imaging (MRI)-guided second near-IR photothermal ferroptosis cancer therapy. Fe₃O₄@Cu_1.77Se remains stable in physiological conditions, but disintegrates to increase reactive intratumoral ferrous supply for elevated hydroxyl radical generation by Fenton reaction and GSH depletion in response to overexpressed matrix metalloproteinases in tumor microenvironment, leading to amplified ferroptosis of tumor cells as well as enhanced T₂-weighted MRI contrast. Further integration with second near-IR photoirradiation to generate localized heat not only triggers effective photothermal therapy and photoacoustic imaging but more importantly, potentiates Fenton reaction to promote ferroptotic tumor cell death. Such synergism leads to the polarization of tumor-associated macrophage from the tumor-promoting M2 type to the tumor-killing M1 type, and induces the immunogenic cells death of tumor cells, which in turn promotes the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumor, contributing to significant tumor suppression. This study presents a novel activatable ferrous nanotheranostics for spatial-temporal control over antitumor ferroptosis responses.     

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.     

Folic‐Acid‐Mediated Functionalized Gold Nanocages for Targeted Delivery of Anti‐miR‐181b in Combination of Gene Therapy and Photothermal Therapy against Hepatocellular Carcinoma

Therapeutic strategies based on modulation of microRNAs (miRNAs) activity hold much promise for cancer therapy, but for clinical applications, the efficient delivery of miRNAs to tumor cells or tumor tissues remains a great challenge. In this work, microRNA‐181b inhibitor (anti‐miR‐181b) is successfully condensed into polyethyleneimine (PEI)‐modified and folate receptor (FR)‐targeted PEGylated gold nanocages (AuNCs). This delivery system is designated as anti‐miR‐181b/PTPAuNCs nanocomplexes (PTPAuNC‐NPs), which begin with chemical modification of AuNCs with SH‐PEG₅₀₀₀‐folic acid (SH‐PEG₅₀₀₀‐FA) and SH‐PEG₅₀₀₀ through a gold–sulfur bond, followed by conjugating PEI using lipoic acid as a linker. Finally anti‐miR‐181b is condensed via electrostatic interactions. In vitro and in vivo experiments show that PTPAuNC‐NPs can efficiently deliver anti‐miR‐181b into target sites to suppress tumor growth, and considerably decrease tumor volumes in SMMC‐7721 tumor‐bearing nude mice under near‐infrared radiation. All these results suggest that PTPAuNC‐NP gene delivery system with combination of gene therapy and photothermal therapy will be of great potential use in future cancer therapy.     

Near‐Infrared Light‐Encoded Orthogonally Triggered and Logical Intracellular Release Using Gold Nanocage@Smart Polymer Shell

Gold nanocages (AuNCs) with hollow interiors, porous walls, and tunable localized surface plasmon resonance (LSPR) peaks in the NIR region represent a promising platform for therapeutic applications, and can be used for orthogonally triggered release by choosing the right laser according to the AuNC's LSPR. AuNCs are prepared with different LSPRs and covered with a smart polymer shell. Laser irradiation in resonance with the LSPR can trigger the release of a pre‐loaded effector. As a proof of concept, enzyme and substrate (prodrug) are selectively released from two different AuNCs. Enzymatic reactions only occur after successful opening of both types of AuNC capsules. The system acts as an “AND” logic gate. Furthermore, if the AuNC is loaded with isoenzyme or enzyme inhibitor, an “OR” or “INHIBIT” logic gate operation is achieved. To the best of our knowledge, no reports have combined NIR light‐encoded orthogonally triggered release with “prodrug” activation processes to realize defined different logic operations for regulating the dosage of active drug in a specific region. The design is simple and spatial/temporal to control, and provides new insights into developing NIR light‐encoded, logically controlled, intracellular release systems.     

Multifunctional Carbon–Silica Nanocapsules with Gold Core for Synergistic Photothermal and Chemo‐Cancer Therapy under the Guidance of Bimodal Imaging

Carbon‐based nanomaterials have been developed for photothermal cancer therapy, but it is still a great challenge to fabricate their multifunctional counterparts with facile methods, good biocompatibility and dispersity, and high efficiency for cancer theranostics. In this work, an alternative multifunctional nanoplatform is developed based on carbon–silica nanocapsules with gold nanoparticle in the cavity (Au@CSN) for cancer theranostics. The encapsulated chemodrug doxorubicin can be released from the Au@CSN with mesoporous and hollow structure in a near‐infrared light and pH stimuli‐responsive manner, facilitating spatiotemporal therapy to decrease off‐target toxicity. The nanocapsules with efficient photothermal conversion and excellent biocompatibility achieve a synergistic effect of photothermal and chemotherapy. Furthermore, the nanocapsules can act as a multimodal imaging agent of computed tomography and photoacoustic tomography imaging for guiding the therapy. This new design platform can provide a promising strategy for precise cancer theranostics.     

Gold Nanorods Electrostatically Binding Nucleic Acid Probe for In Vivo MicroRNA Amplified Detection and Photoacoustic Imaging‐Guided Photothermal Therapy

Developing a comprehensive platform which has both diagnosis and therapeutic strategies is necessary for efficient tumor treatment. In this work, a F uel I mproved micro R NA E xplorer (FIRE) probe with signal amplification capability is designed for sensitive detection of microRNA‐21 (miR‐21), which is upregulated in most tumor cells. Besides, FIRE could be loaded by polyethylenimine (PEI)‐modified gold nanorods (AuNR‐PEI) via facile electrostatic interaction, which could avoid the complicated processes commonly used to covalently conjugate nucleic acid probes onto AuNRs. The as‐fabricated AuNR‐PEI/FIRE system could efficiently distinguish tumor cells from non‐tumor cells. The fluorescence signals in MCF‐7 breast carcinoma and HeLa cervical carcinoma cells treated with AuNR‐PEI/FIRE are enhanced 7‐ and 4.5‐fold, respectively, compared with non‐amplification system. AuNR‐PEI/FIRE improves tumor detection ability in vivo and exhibits excellent tumor inhibition efficacy under the fluorescence imaging and photoacoustic imaging guided photothermal therapy. This is the first time to utilize the combined application of amplified nucleic acid detection and photothermal effect derived from gold nanorods together with PA imaging in a facile manner to provide a promising theranostic strategy for accurate diagnosis and tumor therapy.     

金纳米微粒的光学性质及其在生物成像和光热疗法中的应用

作为生物探针,纳米微粒以其独特的光学性质,易控的表面化学能力,在基于生物成像和诊断的分子生物学和医学领域中引起越来越广泛的关注.贵金属,尤其是金纳米微粒,由于其表面等离子体共振(SPR)等强吸收和发光特性,在生物组织成像,癌症的诊断和治疗中存在着巨大的应用前景.结合配体的金纳米微粒能够特异性地标记癌症细胞上的受体,并提供特定分子的特有信息,进行生物成像和癌症检测.另外,金纳米微粒能够有效地吸收光能量进行局部加热,导致蛋白质变性,并致细胞死亡.主要回顾各种不同尺寸和形状的金纳米微粒的光学特性,以及选择性标记的金纳米微粒在生物成像,癌症诊断和光热疗法中的研究进展.     

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus‐responsive, RBC‐based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near‐infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light‐induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC‐based cancer cell targeted drug delivery and light‐controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.     

Nanostructural Control Enables Optimized Photoacoustic–Fluorescence–Magnetic Resonance Multimodal Imaging and Photothermal Therapy of Brain Tumor

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near‐infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF‐cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF‐cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.     

High‐Security Nanocluster for Switching Photodynamic Combining Photothermal and Acid‐Induced Drug Compliance Therapy Guided by Multimodal Active‐Targeting Imaging

High‐security nanoplatform with enhanced therapy compliance is extremely promising for tumor. Herein, using a simple and high‐efficient self‐assembly method, a novel active‐targeting nanocluster probe, namely, Ag₂S/chlorin e6 (Ce6)/DOX@DSPE‐mPEG₂₀₀₀‐folate (ACD‐FA) is synthesized. Experiments indicate that ACD‐FA is capable of specifically labeling tumor and guiding targeting ablation of the tumor via precise positioning from fluorescence and photoacoustic imaging. Importantly, the probe is endowed with a photodynamic “on‐off” effect, that is, Ag₂S could effectively quench the fluorescence of chlorin e6 (89.5%) and inhibit release of ¹O₂ (92.7%), which is conducive to avoid unwanted phototoxicity during transhipment in the body, and only after nanocluster endocytosed by tumor cells could release Ce6 to produce ¹O₂. Moreover, ACD‐FA also achieves excellent acid‐responsive drug release, and exhibits eminent chemo‐photothermal and photodynamic effects upon laser irradiation. Compared with single or two treatment combining modalities, ACD‐FA could provide the best cancer therapeutic effect with a relatively low dose, because it made the most of combined effect from chemo‐photothermal and controlled photodynamic therapy, and significantly improves the drug compliance. Besides, the active‐targeting nanocluster notably reduces nonspecific toxicity of both doxorubicin and chlorin e6. Together, this study demonstrates the potency of a newly designed nanocluster for nonradioactive concomitant therapy with precise tumor‐targeting capability.     

Near‐Infrared Triggered Release of uPA from Nanospheres for Localized Hyperthermia‐Enhanced Thrombolysis

Currently, most thrombolytic agents are limited by short circulation time and excessive dose needed for clinical therapy, which increases lethal risk for intracranial hemorrhage. Here, a near‐infrared‐triggered, controlled‐release system, using gold@mesoporous silica core–shell nanospheres (Au@MSNs) with phase‐changed material 1‐tetradecanol, is formulated to release urokinase plasminogen activators (uPA) on demand. The prepared system presents a sensitive system for releasing uPA, owing to an elevated temperature created by Au@MSNs‐induced photothermal effect. For in vitro study, a 3D printed vein vasculature is designed and fabricated to simulate the thrombolysis of system in blood vessel. Murine tail thrombus model is also built to evaluate thrombolysis in vivo. Consequently, localized hyperthermia is validated to possess an effective enhancement for thrombolysis. Therefore, according to the results, the fabricated system demonstrates two aspects of potential superiority: controlled uPA release for reducing risk of side effects, and hyperthermia‐enhanced thrombolysis locally for decreasing drug dosage. Assisted with thermal thrombolysis, the present formulated system shows a high efficiency, on‐demand drug release, and thus a safer protocol for thrombolytic therapy, which fits the developing trends of precision medicine.     

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.     

Hydroxyl‐Rich Polycation Brushed Multifunctional Rare‐Earth‐Gold Core–Shell Nanorods for Versatile Therapy Platforms

It is of great significance to develop a multifunctional imaging‐guided therapeutic platform with ideal resolution and sensitivity. Notably, rare‐earth (RE) nanoparticles are attractive candidates for multimodal imaging due to their unique optical and magnetic properties. In this work, a rational design of hierarchical nanohybrids employing RE‐Au hetero‐nanostructures is proposed. 1D RE nanorods are adopted as the core to facilitate cellular internalization with the coating of gold nanoshells for photothermal performances. Hydroxyl‐rich polycations with low cytotoxicity are grafted onto the surface of RE‐Au to produce RE‐Au‐PGEA (ethanolamine‐functionalized poly(glycidyl methacrylate)) nanohybrids with impressive gene transfection capability. Given the virtues of all the components, the feasibility of RE‐Au‐PGEA for multifunctional photoacoustic, computed tomography, magnetic resonance, upconversion luminescence imaging, and complementary photothermal therapy/gene therapy therapy is investigated in detail in vitro and in vivo. The visualization of the therapeutic processes with comprehensive information renders RE‐Au‐PGEA nanohybrid an intriguing platform to realize enhanced antitumor efficiency.     

Near‐Infrared Light‐Absorptive Stealth Liposomes for Localized Photothermal Ablation of Tumors Combined with Chemotherapy

Although near‐infrared (NIR) light‐absorbing organic dyes have recently been proposed for photothermal ablation of tumors, their clinical applications have often been hampered by problems such as low water solubility and minimal tissue absorption. Rapid development of nanotechnology provides various novel nanostructures to address these issues. In this work, doxorubicin (DOX)‐loaded stealth liposomes are engineered through the incorporation of an NIR‐absorptive heptamethine indocyanine dye IR825 into the thermoresponsive liposomes for photothermal/chemo combined cancer therapy. It is demonstrated that the lipid nanostructure can enhance the bioavailability of water‐insoluble IR825 for efficient photothermal treatment, while delivering the anticancer drug doxorubicin to achieve simultaneous anticancer medication. The combined treatment of photothermal ablation and chemotherapy synergistically improves the overall cancer cell killing efficiency, which can be of future clinical interest.     

Novel Redox‐Responsive Polymeric Magnetosomes with Tunable Magnetic Resonance Property for In Vivo Drug Release Visualization and Dual‐Modal Cancer Therapy

Monitoring of in vivo drug release from nanotheranostics by noninvasive approaches remains very challenging. Herein, novel redox‐responsive polymeric magnetosomes (PolyMags) with tunable magnetic resonance imaging (MRI) properties are reported for in vivo drug release monitoring and effective dual‐modal cancer therapy. The encapsulation of doxorubicin (DOX) significantly decreases PolyMags' T₂‐contrast enhancement and transverse relaxation rate R₂, depending on the drug loading level. The T₂ enhancement and R₂ can be recovered once the drug is released upon PolyMags' disassembly. T₂‐ and T₂*‐MRI and diffusion‐weighted imaging (DWI) are utilized to quantitatively study the correlation between MRI signal changes and drug release, and discover the MR tuning mechanisms. The in vivo drug release pattern is visualized based on such tunable MRI capability via monitoring the changes in T₂‐weighted images, T₂ and T₂* maps, and R₂ and R₂* values. Interestingly, the PolyMags possess excellent photothermal effect, which can be further enhanced upon DOX loading. The PolyMags are highly efficacious to treat breast tumors on xenograft model with tumor‐targeted photothermal‐ and chemotherapy, achieving a complete cure rate of 66.7%. The concept reported here is generally applicable to other micellar and liposomal systems for image‐guided drug delivery and release applications toward precision cancer therapy.     

Metal‐Organic‐Framework‐Coated Optical Fibers as Light‐Triggered Drug Delivery Vehicles

Physical delivery of anticancer drugs in controlled anatomic locations can complement the advances being made in chemo‐selective therapies. To this end, an optical fiber catheter is coated in a thin layer of metal organic framework UiO‐66 and the anticancer drug 5‐Fluorouracil (5‐FU) is deposited within the pores. Delivery of light of appropriate wavelength through the fiber catheter is found to trigger the release of 5‐FU on demand, offering a new route to localized drug administration. The system exhibits great potential with as much as 110 × 10^?6 m of 5‐FU delivered within 1 min from one fiber.     

High‐Security Multifunctional Nano‐Bismuth‐Sphere‐Cluster Prepared from Oral Gastric Drug for CT/PA Dual‐Mode Imaging and Chemo‐Photothermal Combined Therapy In Vivo

Multifunctional nanoprobes that can be applied for real‐time monitoring or precision treatment of tumors have received wide interest among researchers. However, most of these nanoprobes are obtained through chemical synthesis, and thereby may contain toxic residues or harmful reagents. In this article, a nano‐bismuth‐sphere‐cluster (Bi) is synthesized via a one‐step method (after an irradiation with ultra‐violet) and is then applied in dual‐mode computed tomography/photoacoustic imaging. Bismuth potassium citrate granules, which is a common gastric drug that is highly safe and has a low price (<1 China Yuan/g), is used as the only raw material. The results show that the Bi cluster has good stability with sizes of about 25–55 nm, and a photothermal conversion efficiency as high as 39.67%. After being adsorbed onto doxorubicin, the Bi cluster can be used directly in animal experiments. Due to the effect of enhanced permeability and retention, the probe can easily enter tumor cells. Drug release can be controlled by a near‐infrared laser and the acidic environment of tumor cells, which indicates that the combined chemo‐photothermal therapy is achieved. This work presents a new dual‐mode bio‐imaging and combined chemo‐photothermal therapeutic nanoprobe that can be applied in theragnostics for tumors.     

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.     

Light‐Triggered Retention and Cascaded Therapy of Albumin‐Based Theranostic Nanomedicines to Alleviate Tumor Adaptive Treatment Tolerance

Tumor adaptive treatment tolerance associated with chemotherapy originates from low tumor accumulation and adverse effects and remains a formidable challenge for cancer therapy. Herein, human serum albumin (HSA)‐based nanomedicines modified with diazirine and loaded with indocyanine green (ICG) and tirapazamine (TPZ), denoted as ICG/TPZ@HSA dNMs are developed. The obtained ICG/TPZ@HSA dNMs can efficiently eradicate the tumors through a cascade of synergistic events triggered by the sequential irradiation of lasers in the tumor area. Upon a 405 nm laser irradiation, the ICG/TPZ@HSA dNMs are able to form aggregates via crosslinking and thus realized enhanced tumor site accumulation and prolonged retention time. The following irradiation at tumor area with an 808 nm laser‐generated local hyperthermia and reactive oxygen species, which results in efficient tumor ablation and increased local hypoxia in the tumor microenvironment. The resulted local hypoxia further activates the initially nontoxic TPZ to a highly cytotoxic derivative, by which precisely bioactivated chemotherapy is achieved following the phototherapy. Thus, upon the laser irradiations, a cascade of aggregation, phototherapy, and bioactivated chemotherapy is successfully triggered, which achieves efficient precise eradication of tumors without detectable side effects in vivo.