A bioinspired doxorubicin-carried albumin Nanocage against aggressive Cancer via systemic targeting of tumor and lymph node metastasis.

Cancer metastasis and recurrence are obstacles to successful treatment of aggressive cancer. To address this challenge, chemotherapy is indispensable as an essential part of comprehensive cancer treatment, particularly for subsequent therapy after surgical resection. However, small-molecule drugs for chemotherapy always cause inadequate efficacy and severe side effects against cancer metastasis and recurrence caused by lymph node metastases. Here, we developed doxorubicin-carried albumin nanocages (Dox-AlbCages) with appropriate particle sizes and pH/enzyme-responsive drug release for tumor and lymph node dual-targeted therapy by exploiting the inborn transport properties of serum albumin. Inspired by the protein-templated biomineralization and remote loading of doxorubicin into liposomes, we demonstrated the controlled synthesis of Dox-AlbCages via the aggregation or crystallization of doxorubicin and ammonium sulfate within albumin nanocages using a biomineralization strategy. Dox-AlbCages allowed efficient encapsulation of Dox in the core protected by the albumin corona shell, exhibiting favorable properties for enhanced tumor and lymph node accumulation and preferable cellular uptake for tumor-specific chemotherapy. Intriguingly, Dox-AlbCages effectively inhibited tumor growth and metastasis in orthotopic 4T1 breast tumors and prevented postsurgical tumor recurrence and lung metastasis. At the same time, Dox-AlbCages had fewer side effects than free Dox. This nanoplatform provides a facile strategy for designing tumor- and lymph node-targeted nanomedicines for suppressing cancer metastasis and recurrence.

Harness arsenic in medicine: current status of arsenicals and recent advances in drug delivery.

INTRODUCTION: Arsenicals have a special place in the history of human health, acting both as poison and medicine. Having been used to treat a variety of diseases in the past, the success of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) in the last century marked its use as a drug in modern medicine. To expand their role against cancer, there have been clinical uses of arsenicals worldwide and progress in the development of drug delivery for various malignancies, especially solid tumors. AREAS COVERED: In this review, conducted on Google Scholar [1977-2024], we start with various forms of arsenicals, highlighting the well-known ATO. The mechanism of action of arsenicals in cancer therapy is then overviewed. A summary of the research progress in developing new delivery approaches (e.g. polymers, inorganic frameworks, and biomacromolecules) in recent years is provided, addressing the challenges and opportunities in treating various malignant tumors. EXPERT OPINION: Reducing toxicity and enhancing therapeutic efficacy are guidelines for designing and developing new arsenicals and drug delivery systems. They have shown potential in the fight against cancer and emerging pathogens. New technologies and strategies can help us harness the potency of arsenicals and make better products.

A Bioorthogonal Decaging Chemistry of N-Oxide and Silylborane for Prodrug Activation both In Vitro and In Vivo.

Bioorthogonal decaging chemistry with both fast kinetics and high efficiency is highly demanded for in vivo applications but remains very sporadic. Herein, we describe a new bioorthogonal decaging chemistry between N-oxide and silylborane. A simple replacement of "C" in boronic acid with "Si" was able to substantially accelerate the N-oxide decaging kinetics by 106 fold (k2: up to 103 M-1 s-1). Moreover, a new N-oxide-masked self-immolative spacer was developed for the traceless release of various payloads upon clicking with silylborane with fast kinetics and high efficiency (>90%). Impressively, one such N-oxide-based self-assembled bioorthogonal nano-prodrug in combination with silylborane led to significantly enhanced tumor suppression effects as compared to the parent drug in a 4T1 mouse breast tumor model. In aggregate, this new bioorthogonal click-and-release chemistry is featured with fast kinetics and high efficiency and is perceived to find widespread applications in chemical biology and drug delivery.

Reactive Oxygen Species-Activated Metal-Free Carbon Monoxide Prodrugs for Targeted Cancer Treatment.

Carbon monoxide has shown promise as a therapeutic agent against cancers. Reactive oxygen species (ROS)-activated CO prodrugs are highly demanded for targeted cancer treatment but remain sporadic. In addition, little attention is on how the release rate affects CO's biological effects. Herein, we describe a new type of ROS-activated metal-free CO prodrug, which releases CO with tunable release rates in response to multiple ROS and exhibits very pronounced tumor suppression effects in a mouse 4t1 breast tumor model. Importantly, for the first time, we observe both in vitro and in vivo that CO release rate has a direct impact on its antiproliferative potency and a correlation between release rate and antiproliferative activity is observed. In aggregates, our results not only deliver ROS-sensitive CO prodrugs for cancer treatment but also represent a promising starting point for further in-depth studies of how CO release kinetics affect anticancer activity.

Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation.

The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor ß (TGFß) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy.

A pH-Activatable Copper-Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo-Immunotherapy against Aggressive Cancers.

Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic-utilization efficiency, and undesired off-target toxicity. Herein, it is reported that peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2 O2 into hydroxyl radicals (·OH) in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.

Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging.

Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.

Albumin-templated platinum (II) sulfide nanodots for size-dependent cancer theranostics.

Transition-metal chalcogenides, such as noble metal chalcogenides, hold tremendous potential as efficient agents for photo-induced cancer theranostics due to their unique physicochemical properties. However, a critical bottleneck still lies in exploring simple and controllable methods to synthesize noble metal chalcogenides especially PtS for in vivo photo-induced cancer imaging and simultaneous therapy. Herein, we proposed the albumin-templated synthesis of size-controllable platinum (II) sulfide nanodots (PtS-NDs) for multimodal cancer imaging and potent photothermal therapy. PtS-NDs were precisely synthesized with a tunable size ranging from 2.1 nm to 4.5 nm through a thermodynamically controlled growth inside albumin nanocages. PtS-NDs yielded significant near-infrared (NIR) absorbance and outstanding photothermal conversion under NIR laser irradiation, as well as effective resistance to photobleaching, thereby generating remarkable in vivo photoacoustic signals and distinct hyperthermia at tumor site. Moreover, these nanodots possessed efficient cellular uptake and tumor targeting capabilities in a size-dependent manner, thus leading to controllable diagnostic and thermo-therapeutic efficacy. Specifically, PtS-NDs with core diameter of 4.5 nm displayed preferable in vivo photoacoustic and CT imaging with high sensitivity, spatially and anatomically enhanced imaging contrast, together with hyperthermia mediated tumor ablation. Thus, the albumin-templated biomimetic synthesis provided an insightful strategy on fabricating theranostic PtS-NDs for potential clinical applications. STATEMENT OF SIGNIFICANCE: Noble metal chalcogenides especially PtS are of particular importance in the field of precise nanomedicine to improve both accuracy of cancer diagnosis and efficiency of tumor treatment. However, the intensively preclinical investigation of PtS was limited due to the lack of simple and controllable synthetic methods. Here, we report an albumin-templated biomineralization synthesis of platinum (II) sulfide nanodots (PtS-NDs). Specifically, albumin-templated biomineralization of PtS-NDs was induced by the electrostatic interactions between albumin and Pt2+, followed by the nucleation and growth inside the albumin nanocages. The resulting PtS-NDs showed good dispersibility and biosafety, as well as size-dependent photophysical properties and biological behaviors. Therefore, albumin-based biomineralization is a promising and safe strategy to facilely fabricate Pt-based chalcogenide for tumor theranostics.

Hydrophobicity Determines the Bacterial Killing Rate of α-Helical Antimicrobial Peptides and Influences the Bacterial Resistance Development.

Rapid antimicrobial action is an important advantage of antimicrobial peptides (AMPs) over antibiotics, which is also a reason for AMPs being less likely to induce bacterial resistance. However, the structural parameters and underlying mechanisms affecting the bacterial killing rate of AMPs remain unknown. In this study, we performed a structure-activity relationship (SAR) study using As-CATH4 and 5 as templates. We revealed that hydrophobicity, rather than other characteristics, is the critical structural parameter determining the bacterial killing rate of α-helical AMPs. With the hydrophobicity increase, the action rates of AMPs including bacterial binding, lipopolysaccharides neutralization, and outer and inner membrane permeabilization increased. Additionally, the higher hydrophobic AMPs with enhanced bacterial killing rates possess better in vivo therapeutic potency and a lower propensity to induce bacterial resistance. These findings revealed the importance of the bacterial killing rate for AMPs and are of great significance to the design and optimization of AMP-related drugs.

Self-activated arsenic manganite nanohybrids for visible and synergistic thermo/immuno-arsenotherapy.

Arsenotherapy has been clinically exploited to treat a few types of solid tumors despite of acute promyelocytic leukemia using arsenic trioxide (ATO), however, its efficacy is hampered by inadequate delivery of ATO into solid tumors owing to the absence of efficient and biodegradable vehicles. Precise spatiotemporal control of subcellular ATO delivery for potent arsenotherapy thus remains challengeable. Herein, we report the self-activated arsenic manganite nanohybrids for high-contrast magnetic resonance imaging (MRI) and arsenotherapeutic synergy on triple-negative breast cancer (TNBC). The nanohybrids, composed of arsenic­manganese-co-biomineralized nanoparticles inside albumin nanocages (As/Mn-NHs), switch signal-silent background to high proton relaxivity, and simultaneously afford remarkable subcellular ATO level in acidic and glutathione environments, together with reduced ATO resistance against tumor cells. Then, the nanohybrids enable in vivo high-contrast T1-weighted MRI signals in various tumor models for delineating tumor boundary, and simultaneously yield efficient arsenotherapeutic efficacy through multiple apoptotic pathways for potently suppressing subcutaneous and orthotopic breast models. As/Mn-NHs exhibited the maximum tumor-to-normal tissue (T/N) contrast ratio of 205% and tumor growth inhibition rate of 88% at subcutaneous 4T1 tumors. These nanohybrids further yield preferable synergistic antitumor efficacy against both primary and metastatic breast tumors upon combination with concurrent thermotherapy. More importantly, As/Mn-NHs considerably induce immunogenic cell death (ICD) effect to activate the immunogenically "cold" tumor microenvironment into "hot" one, thus synergizing with immune checkpoint blockade to yield the strongest tumor inhibition and negligible metastatic foci in the lung. Our study offers the insight into clinically potential arsenotherapeutic nanomedicine for potent therapy against solid tumors.

Chemiexcitation-Triggered Prodrug Activation for Targeted Carbon Monoxide Delivery.

Photolysis-based prodrug strategy can address some critical drug delivery issues, which otherwise are very challenging to tackle with traditional prodrug strategy. However, the need for external light irradiation significantly hampers its in vivo application due to the poor light accessibility of deep tissue. Herein, we propose a new strategy of chemiexcitation-triggered prodrug activation, wherein a photoresponsive prodrug is excited for drug payload release by chemiexcitation instead of photoirradiation. As such, the bond-cleavage power of photolysis can be employed to address some critical drug delivery issues while obviating the need for external light irradiation. We have established the proof of concept by the successful development of a chemiexcitation responsive carbon monoxide delivery platform, which exhibited specific CO release at the tumor site and pronounced tumor suppression effects. We anticipate that such a concept of chemiexcitation-triggered prodrug activation can be leveraged for the targeted delivery of other small molecule-based drug payloads.

Liposomal cyanine dyes with enhanced nonradiative transition for the synergistic phototherapy of tumors.

Organic photosensitizers are of great interest in cancer diagnosis and treatments such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). However, their poor aqueous solubility, inadequate photostability and unsatisfactory photophysical parameters limit their clinical application. Herein, we report the construction of liposome encapsulating cyanine dye Cypate (Lipo-Cy) with enhanced nonradiative transition for efficient cancer therapy. After being loaded in liposomes, Cypate molecules are spatially confined within the hydrophobic lipid bilayer, thereby causing much better stability, higher photothermal conversion efficiency, and increased singlet oxygen quantum yield than free Cypate via enhanced nonradiative transition through π-π aggregation. Lipo-Cy further enhanced the cellular uptake of Cypate, as well as preferable tumor accumulation and retention, leading to abundant intracellular singlet oxygen and potent hyperthermia at the tumor for effective PTT synergized PDT, even at dosages 10 times less than free Cypate. The Lipo-Cy exhibited superior anticancer efficiency, showing great prospects for clinical translation.

Biomineralized iron oxide-polydopamine hybrid nanodots for contrast-enhanced T1-weighted magnetic resonance imaging and photothermal tumor ablation.

Iron oxide nanoparticles (IO NPs) have become the focus of molecular imaging probes for contrast enhanced magnetic resonance (MR) imaging due to their intrinsic magnetic and biodegradable properties, as well as long blood half-lives and low toxicity. Massive efforts have been made to explore the IO NPs as T2-weighted MR contrast agents, which have high susceptibility to induce a long-range magnetic field that interferes with diagnosis. Thus, the development of IO NPs with potent T1 relaxivity might help in providing an alternative for clinically applied gadolinium chelates. Herein, biomineralized iron oxide-polydopamine hybrid nanodots (IO/PDA-NDs) have been constructed using albumin as the nanoreactors to induce nanoprecipitation and polymerization simultaneously, facilitating T1-weighted contrast-enhancement as well as photothermal therapeutic capability. The IO nanoclusters in IO/PDA-NDs have an r1 relaxivity of 5.79 mM-1 s-1 with a relatively low r2/r1 ratio of 1.71, demonstrating the preferable iron oxide based T1 contrast agents. The high photothermal conversion coefficient and tumor targeting effect of the hybrid nanodots could result in complete tumor ablation efficacy. The biomineralization method provides a promising approach for the integration of tumor diagnosis and treatment to achieve efficient cancer theranostics.

Heavy-Atom-Modulated Supramolecular Assembly Increases Antitumor Potency against Malignant Breast Tumors via Tunable Cooperativity.

Triple-negative breast cancer (TNBC) remains with highest incidence and mortality rates among females, and a critical bottleneck lies in rationally establishing potent therapeutics against TNBC. Here, the self-assembled micellar nanoarchitecture of heavy-atom-modulated supramolecules with efficient cytoplasmic translocation and tunable photoconversion is shown, for potent suppression against primary, metastatic, and recurrent TNBC. Multi-iodinated boron dipyrromethene micelles yield tunable photoconversion into singlet oxygen and a thermal effect, together with deep penetration and subsequent cytoplasmic translocation at the tumor. Tetra-iodinated boron dipyrromethene micelles (4-IBMs) particularly show a distinctly enhanced cooperativity of antitumor efficiency through considerable expressions of apoptotic proteins, potently suppressing subcutaneous, and orthotopic TNBC models, together with reduced oxygen dependence. Furthermore, 4-IBMs yield preferable anti-metastatic and anti-recurrent efficacies through the inhibition of metastasis-relevant proteins, distinct immunogenic cell death, and re-education of M2 macrophages into tumoricidal M1 phenotype as compared to chemotherapy and surgical resection. These results offer insights into the cooperativity of supramolecular nanoarchitectures for potent phototherapy against TNBC.

Serum protein-based nanoparticles for cancer diagnosis and treatment.

Serum protein as naturally essential biomacromolecules has recently emerged as a versatile carrier for diagnostic and therapeutic drug delivery for cancer nanomedicine with superior biocompatibility, improved pharmacokinetics and enhanced targeting capacity. A variety of serum proteins have been utilized for drug delivery, mainly including albumin, ferritin/apoferritin, transferrin, low-density lipoprotein, high-density lipoprotein and hemoglobin. As evidenced by the success of paclitaxel-bound albumin nanoparticles (AbraxaneTM), serum protein-based nanoparticles have gained attractive attentions for precise biological design and potential clinical application. In this review, we summarize the general design strategies, targeting mechanisms and recent development of serum protein-based nanoparticles in the field of cancer nanomedicine. Moreover, we also concisely specify the current challenges to be addressed for a bright future of serum protein-based nanomedicines.

Rationally Designed Monodisperse Gd2 O3 /Bi2 S3 Hybrid Nanodots for Efficient Cancer Theranostics.

Multifunctional nanotheranostic agents are of particular importance in the field of precise nanomedicine. However, a critical challenge remains in the rational fabrication of monodisperse multicomponent nanoparticles with enhanced multifunctional characteristics for efficient cancer theranostics. Here, a rational and facile synthesis of monodisperse Gd2 O3 /Bi2 S3 hybrid nanodots (Gd/Bi-NDs) is demonstrated as a multifunctional nanotheranostic agent using a albumin nanoreactor for computed tomography (CT)/photoacoustics (PA)/magnetic resonance (MR) imaging and simultaneous photothermal tumor ablation. Two nanoprecipitation reactions in one albumin nanoreactor are simultaneously conducted to generate ultrasmall Gd/Bi-NDs with both orthorhombic Bi2 S3 and cubic Gd2 O3 nanostructures. Their hybrid nanostructure generates distinctly enhanced longitudinal relaxivity in the spatially confined albumin nanocage as compared to monocomponent Gd2 O3 nanodots. Moreover, such hybrid nanodots possess multiple desirable characteristics including superior photobleaching resistance, efficient cellular uptake, preferable tumor accumulation, good in vivo clearance, and negligible acute toxicity, thereby leading to complementary PA/CT/MR imaging with spatial and anatomic characteristics, as well as effective photothermal tumor ablation without regrowth. These results represent a promising approach to fabricate monodisperse multicomponent nanotheranostic agents for efficient cancer theranostics.

Rational Design of Conjugated Photosensitizers with Controllable Photoconversion for Dually Cooperative Phototherapy.

High-performance photosensitizers are highly desired for achieving selective tumor photoablation in the field of precise cancer therapy. However, photosensitizers frequently suffer from limited tumor suppression or unavoidable tumor regrowth due to the presence of residual tumor cells surviving in phototherapy. A major challenge still remains in exploring an efficient approach to promote dramatic photoconversions of photosensitizers for maximizing the anticancer efficiency. Here, a rational design of boron dipyrromethene (BDP)-based conjugated photosensitizers (CPs) that can induce dually cooperative phototherapy upon light exposure is demonstrated. The conjugated coupling of BDP monomers into dimeric BDP (di-BDP) or trimeric BDP (tri-BDP) induces photoconversions from fluorescence to singlet-to-triplet or nonradiative transitions, together with distinctly redshifted absorption into the near-infrared region. In particular, tri-BDP within nanoparticles shows preferable conversions into both primary thermal effect and minor singlet oxygen upon near-infrared light exposure, dramatically achieving tumor photoablation without any regrowth through their cooperative anticancer efficiency caused by their dominant late apoptosis and moderate early apoptosis. This rational design of CPs can serve as a valuable paradigm for cooperative cancer phototherapy in precision medicine.

Albumin-coordinated assembly of clearable platinum nanodots for photo-induced cancer theranostics.

Photoactive noble metal nanoparticles are of increasing importance toward personalized cancer therapy in the field of precision nanomedicine. A critical challenge remains in the exploration of clinically potential noble metal nanoparticles for highly efficient cancer theranostics. Here, we introduce albumin-coordinated assembly of clearable Pt nanodots (Pt-NDs) with monodisperse nanostructure as high-performance theranostic agents for imaging-guided photothermal tumor ablation. We precisely manipulate the reduction and growth of tetravalent Pt ions into ultrasmall nanodots through albumin-directed growth kinetics, thereby leading to the synthesis of monodisperse 6.7 nm Pt-NDs with albumin molecules as the corona. Pt-NDs exhibit the surface plasmon resonance at 225 nm with enhanced near-infrared (NIR) absorbance, ideal resistance to photo-bleaching, distinct photoacoustic and X-ray signals, as well as remarkable photothermal effect through non-radiative relaxation under NIR light irradiation. In particular, Pt-NDs possess preferable tumor accumulation, and effective in vivo excretory capability. Thus, these nanodots promote preferable in vivo microscopic photoacoustics and spatially anatomic CT imaging with enhanced contrast, as well as potent hyperthermia-mediated tumor ablation. These findings represent a facile and general approach to fabricate high-performance noble metal nanostructures with clinical potential for cancer theranostics.

Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents.

Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth.