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.

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.

Highly Efficient Far-Red/NIR-Absorbing Neutral Ir(III) Complex Micelles for Potent Photodynamic/Photothermal Therapy.

A critical issue in photodynamic therapy (PDT) is inadequate reactive oxygen species (ROS) generation in tumors, causing inevitable survival of tumor cells that usually results in tumor recurrence and metastasis. Existing photosensitizers frequently suffer from relatively low light-to-ROS conversion efficiency with far-red/near-infrared (NIR) light excitation due to low-lying excited states that lead to rapid non-radiative decays. Here, a neutral Ir(III) complex bearing distyryl boron dipyrromethene (BODIPY-Ir) is reported to efficiently produce both ROS and hyperthermia upon far-red light activation for potentiating in vivo tumor suppression through micellization of BODIPY-Ir to form "Micelle-Ir". BODIPY-Ir absorbs strongly at 550-750 nm with a band maximum at 685 nm, and possesses a long-lived triplet excited state with sufficient non-radiative decays. Upon micellization, BODIPY-Ir forms J-type aggregates within Micelle-Ir, which boosts both singlet oxygen generation and the photothermal effect through the high molar extinction coefficient and amplification of light-to-ROS/heat conversion, causing severe cell apoptosis. Bifunctional Micelle-Ir that accumulates in tumors completely destroys orthotopic 4T1 breast tumors via synergistic PDT/photothermal therapy (PTT) damage under light irradiation, and enables remarkable suppression of metastatic nodules in the lungs, together without significant dark cytotoxicity. The present study offers an emerging approach to develop far-red/NIR photosensitizers toward potent cancer therapy.

Immune Checkpoint Inhibitor-Based Strategies for Synergistic Cancer Therapy.

Immune checkpoint blockade therapy (ICBT) targeting checkpoints, such as, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed death-1 (PD-1), or programmed death-ligand 1 (PD-L1), can yield durable immune response in various types of cancers and has gained constantly increasing research interests in recent years. However, the efficacy of ICBT alone is limited by low response rate and immune-related side effects. Emerging preclinical and clinical studies reveal that chemotherapy, radiotherapy, phototherapy, or other immunotherapies can reprogramm immunologically "cold" tumor microenvironment into a "hot" one, thus synergizing with ICBT. In this review, the working principle and current development of various immune checkpoint inhibitors are summarized, while the interactive mechanism and recent progress of ICBT-based synergistic therapies with other immunotherapy, chemotherapy, phototherapy, and radiotherapy in fundamental and clinical studies in the past 5 years are depicted and highlighted. Moreover, the potential issues in current studies of ICBT-based synergistic therapies and future perspectives are also discussed.

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.

Ultrastable Near-Infrared Nonlinear Organic Chromophore Nanoparticles with Intramolecular Charge Transfer for Dually Photoinduced Tumor Ablation.

Near-infrared (NIR) light-responsive nanoparticles (NPs) of organic photosensitizers (PS) hold great promise as phototherapeutic agents for precision photoinduced cancer therapy. However, highly photostable PS nanoparticles with extraordinary photoconversion capacities are urgently desired to fully realize potent phototherapy. Here, NIR nonlinear organic chromophore nanoparticles (NOC-NPs) are shown as single-component PS for dually cooperative phototherapy. Upon 785 nm irradiation, excited NOC-NPs pass through intrinsic intramolecular charge transfer (ICT) channel to generate both abundant singlet oxygen and local hyperthermia, affording synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) for tumor ablation. Furthermore, NOC-NPs exhibit dramatic photostability, enhanced cellular uptake, effective cytoplasmic translocation, as well as preferable tumor accumulation, further ensuring favorable in vivo singlet oxygen generation and hyperthermia for photoinduced tumor ablation. Thus, NOC-NPs may represent novel high-performance PS for synergistic photoinduced cancer therapy, providing new insights into the development of potent PS for clinical translation.

Amphiphilic BODIPY dye aggregates in polymeric micelles for wavelength-dependent photo-induced cancer therapy.

Near-infrared (NIR) light-responsive nanoparticles of organic small-molecule dyes hold great promise as phototherapeutic dyes (PDs) for clinical translation due to their intrinsic merits, including well-defined structure, high purity, and good reproducibility. However, they have been explored with limited success in the development of photostable NIR PDs with extraordinary photoconversion for highly effective phototherapy. Herein, we have described amphiphilic BODIPY dye aggregates within the polymeric micelles (Micelles) as potent bifunctional PDs for dually cooperative phototherapy under NIR irradiation. Micelles possessed an intensive NIR absorption, high photostability, and favorable non-radiative transition, thereby exhibiting both remarkable singlet oxygen generation and photothermal effect under NIR light irradiation. Besides, Micelles had preferable cellular uptake, effective cytoplasmic drug translocation as well as enhanced tumor accumulation. Owing to the combined virtues, Micelles showed clinical potential as bifunctional PDs for photo-induced cancer therapy. This work thus provides a facile strategy to exploit advanced PDs for practical phototherapeutic applications.

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.

Size-Tunable Gd2O3@Albumin Nanoparticles Conjugating Chlorin e6 for Magnetic Resonance Imaging-Guided Photo-Induced Therapy.

Protein nanoparticles as nanocarriers are of particular interest in the field of cancer therapy. Nevertheless, so far a facile fabrication of theranostic protein nanoparticles have been explored with limited success for cancer imaging and therapy. In this work, we demonstrate the controllable synthesis of size-tunable Gd2O3@albumin conjugating photosensitizer (PS) (GA-NPs) using hollow albumin as the nanoreactor for magnetic resonance imaging (MRI)-guided photo-induced therapy. The growth of Gd2O3 nanocrystals within the hollow nanoreactors is well regulated through reaction time, and a typical PS (e.g. chlorin e6) is further conjugated with the protein corona of the nanoreactor through facile chemical coupling, followed by the formation of theranostic GA-NPs. GA-NPs exhibit good longitudinal relaxivity, ideal photostability, enhanced cellular uptakes, and preferable size-dependent tumor accumulation. Moreover, GA-NPs effectively generate remarkable photothermal effect, intracellular reactive oxygen species from Ce6, and subsequent cytoplasmic drug translocation, thereby leading to severe synergistic photothermal and photodynamic cell damages. Consequently, GA-NPs exhibit an in vivo size-dependent MRI capacity with enhanced imaging contrast for effective tumor localization, and also generate a potent synergistic photodynamic therapy/photothermal therapy efficacy under irradiation owing to their enhanced tumor accumulation and strong photo-induced cytotoxicity. These results suggest that GA-NPs can act as a promising theranostic protein nanoplatform for cancer imaging and photo-induced therapy.

Indocyanine Green Loaded Magnetic Carbon Nanoparticles for Near Infrared Fluorescence/Magnetic Resonance Dual-Modal Imaging and Photothermal Therapy of Tumor.

Malignant tumor incidences have been rapidly rising recently and are becoming a serious threat to human health. Herein, a multifunctional cancer targeted theranostic nanoplatform is developed by in situ growth of iron oxide magnetic nanoparticles on carbon nanoparticles, and then loaded with fluorescent dye indocyanine green (ICG@MCNPs). The loading of ICG on the nanoplatform significantly improves its photostability, and hence facilitates long-term near-infrared fluorescence (NIRF) imaging and efficient photothermal therapy (PTT) of tumor. The in vivo NIRF imaging reveals that ICG@MCNPs can be targeted to the tumor site. Moreover, in vivo magnetic resonance imaging also confirmed the efficient accumulation of ICG@MCNPs in the tumor site. Inspiringly, the subsequent PTT of tumor-bearing mice is achieved, as evidenced by the complete ablation of the tumor and the recovery of the physiological indexes to normal levels. Benefitting from its low-cost, simple preparation, and excellent dual-modal imaging and therapy, the ICG@MCNPs-based theranostic nanoplatform holds great promise in tumor-targeted nanomedicine.

Photoconversion-Tunable Fluorophore Vesicles for Wavelength-Dependent Photoinduced Cancer Therapy.

Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength-dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J-type and H-type, thereby causing red-shifted absorption into near-infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen-synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength-dependent photoinduced cancer therapy.

Size-Dependent Ag2S Nanodots for Second Near-Infrared Fluorescence/Photoacoustics Imaging and Simultaneous Photothermal Therapy.

Ag2S nanoparticles are increasingly important in biomedicine, such as in cancer imaging. However, there has been only limited success in the exploration of theranostic Ag2S nanoparticles for photoinduced cancer imaging and simultaneous therapy. Here we report size-dependent Ag2S nanodots (NDs) with well-defined nanostructure as a theranostic agent for multimodal imaging and simultaneous photothermal therapy. The NDs are precisely synthesized through carefully controlled growth of Ag2S in hollow human serum albumin nanocages. These NDs produce effective fluorescence in second near-infrared (NIR-II) region, distinct photoacoustic intensity, and good photothermal conversion in a size-dependent manner under light irradiation, thereby generating sufficient in vivo fluorescence and photoacoustic signals as well as potent hyperthermia at tumors. Moreover, Ag2S NDs possess ideal resistance to photobleaching, effective cellular uptake, preferable tumor accumulation, and in vivo elimination, thus facilitating NIR-II fluorescence/photoacoustics imaging with both ultrasensitivity and microscopic spatial resolution and simultaneous photothermal tumor ablation. These findings provide insight into the clinical potential of Ag2S nanodots for cancer theranostics.

Cyanine-Anchored Silica Nanochannels for Light-Driven Synergistic Thermo-Chemotherapy.

Smart nanoparticles are increasingly important in a variety of applications such as cancer therapy. However, it is still a major challenge to develop light-responsive nanoparticles that can maximize the potency of synergistic thermo-chemotherapy under light irradiation. Here, spatially confined cyanine-anchored silica nanochannels loaded with chemotherapeutic doxorubicin (CS-DOX-NCs) for light-driven synergistic cancer therapy are introduced. CS-DOX-NCs possess a J-type aggregation conformation of cyanine dye within the nanochannels and encapsulate doxorubicin through the π-π interaction with cyanine dye. Under near-infrared light irradiation, CS-DOX-NCs produce the enhanced photothermal conversion efficiency through the maximized nonradiative transition of J-type Cypate aggregates, trigger the light-driven drug release through the destabilization of temperature-sensitive π-π interaction, and generate the effective intracellular translocation of doxorubicin from the lysosomes to cytoplasma through reactive oxygen species-mediated lysosomal disruption, thereby causing the potent in vivo hyperthermia and intracellular trafficking of drug into cytoplasma at tumors. Moreover, CS-DOX-NCs possess good resistance to photobleaching and preferable tumor accumulation, facilitating severe photoinduced cell damage, and subsequent synergy between photothermal and chemotherapeutic therapy with tumor ablation. These findings provide new insights of light-driven nanoparticles for synergistic cancer therapy.

Bifunctional Platinated Nanoparticles for Photoinduced Tumor Ablation.

Bifunctional self-assembled nanoparticles with a platinated fluorophore core with ultra-low radiative transition are developed, which can generate both singlet oxygen and the photothermal effect for synergistic photodynamic and photothermal therapy with tumor ablation.

Dually pH/Reduction-Responsive Vesicles for Ultrahigh-Contrast Fluorescence Imaging and Thermo-Chemotherapy-Synergized Tumor Ablation.

Smart nanocarriers are of particular interest as nanoscale vehicles of imaging and therapeutic agents in the field of theranostics. Herein, we report dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer with near-infrared cyanine dye and anticancer drug. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasma, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy.

Smart Albumin-Biomineralized Nanocomposites for Multimodal Imaging and Photothermal Tumor Ablation.

Smart cyanine-grafted gadolinium oxide nanocrystals (Cy-GdNCs) obtained by albumin-based biomineralization are shown to be theranostic nanocomposites, with promising properties for trimodal near-infrared fluorescence/photoacoustics/magnetic-resonance imaging-guided photothermal tumor ablation.