A Red Light Activatable Multifunctional Prodrug for Image‐Guided Photodynamic Therapy and Cascaded Chemotherapy

A multifunctional prodrug, designated as TPP‐L‐GEM, is fabricated to realize image‐guided in situ tumor photodynamic therapy (PDT) with red light activatable chemotherapy. Gemcitabine is conjugated with a fluorescent photosensitizer, meso‐tetraphenylporphyrin (TPP), by a reactive oxygen species cleavable thioketal linker. Under the irradiation of low‐energy red light, TPP can generate singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the thioketal linkage can be cleaved by singlet oxygen and result in a cascaded gemcitabine release, causing sustained cell damage by chemotherapy. With the combination of PDT and cascaded chemotherapy, TPP‐L‐GEM shows significant tumor therapeutic efficacy in vitro and in vivo. Furthermore, the inherent fluorescent property of TPP endows the TPP‐L‐GEM prodrug with noninvasive drug tracking capability, which is favorable for image‐guided tumor therapy.     

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.     

Disrupting Intracellular Iron Homeostasis by Engineered Metal-Organic Framework for Nanocatalytic Tumor Therapy in Synergy with Autophagy Amplification-Promoted Ferroptosis

Metal-organic frameworks (MOFs) featuring good biocompatibility and tunable microstructures are developed to generate reactive oxygen species (ROS) for nanocatalytic therapy. However, the relatively low catalytic activity of MOF and intracellular ion homeostasis, a self-protective mechanism to resist the intracellular accumulation of metal ions, results in the undesirable efficacy of tumor therapy. Herein, a therapeutic strategy is introduced of breaking intracellular iron homeostasis for nanocatalytic therapy in synergy with autophagy amplification-promoted ferroptosis, based on etched MOF nanocatalyst (denoted COS@MOF), which is self-etched by thiamine pyrophosphate (TPP) and further modified with autophagy agonist chitosan oligosaccharides (COS). Such self-etched MOF exhibit an open cavity structure that is more conducive to adsorbing reactive molecules and producing more active sites, and an enhanced Fe(II)/Fe(III) ratio, reinforcing catalytic activity for ROS generation. The catalytic process of COS@MOF can be accelerated by overexpressed endogenous hydrogen sulfide (H₂S) within colorectal tumors which reduces Fe³⁺ into more active Fe²⁺. In vitro and in vivo results demonstrate that COS@MOF amplifies autophagy to break iron homeostasis for facilitating ROS production to promote ferroptosis, achieving synergetic nanocatalytic/ferroptosis tumor therapy. This study provides a promising paradigm to elevate MOF-based catalytic performance in synergy with autophagy amplification-promoted ferroptosis for enhanced therapeutic efficacy.     

Ferroptosis and Pyroptosis Co-Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.     

Nanoscintillator-Mediated X-Ray-Triggered Boosting Transformation of Fe3+ into Fe2+ for Enhancing Tumor Ferroptosis/Immunotherapy

Ferroptosis therapy induced by iron-catalyzed Fenton reaction has offered enormous opportunities for tumor therapy. Unfortunately, high catalytic activity ferrous (Fe²⁺)-based therapeutic agent has remained challenging due to the instability of Fe²⁺. Herein, an X-ray-activated Fe²⁺ supply platform, termed “PFCN”, containing the core of CaWO₄ nanoscintillator to emit ultraviolet (UV) light and Fe₃O₄ decorated on the surface to deliver excessive Fe²⁺ is proposed. Under X-ray excitation, the UV light emitted by CaWO₄ can catalyze ferric (Fe³⁺) to generate Fe²⁺, which further cascades the Fenton reaction to induce highly toxic hydroxyl radicals generation. More importantly, immunogenic cell death-associated immunotherapy is simultaneously triggered during this process. Experiments conducted in vitro and in vivo revealed that X-ray-triggered PFCN shows superior tumor therapeutic efficacy, contributing i) enhanced radiotherapy; ii) X-ray-activated ferroptosis therapy; and iii) ferroptosis/radiotherapy-induced immunotherapy. Besides, PFCN can be utilized as an MR/CT dual-mode imaging contrast agent for tumor diagnosis and treatment monitoring. The study provides a novel example of an X-ray-activated ferrous-regeneration platform for imaging-guided augmenting tumor ferroptosis/immunotherapy     

Rigid Shell Decorated Nanodevice with Fe/H2O2 Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy

The overexpressed glutathione peroxidase4 (GPX4) and insufficient H₂O₂ in tumor cells weaken ferroptosis therapy and the elicited anticancer immune response. Herein, a rigid metal-polyphenol shell decorated nanodevice ssPPE_Lap@Fe-TA is constructed to successfully overcome the drawbacks of ferroptosis therapy. The ssPPE_Lap@Fe-TA consists of a rigid Fe-TA network-based shell and disulfide-containing polyphosphoester (ssPPE) core with β-lapachone loading. The rigid Fe-TA network-based shell of ssPPE_Lap@Fe-TA enables its efficient internalization by tumor cell and then disintegrates in the acidic endosome/lysosome to initiate Fe³⁺/Fe²⁺ conversion-driven ferroptosis. The ssPPE core will deplete glutathione (GSH) via the disulfide-thiol exchange reaction to inactivate GPX4, and also trigger the release of β-lapachone to significantly increase intracellular H₂O₂ and then promote Fe³⁺-mediated Fenton reaction, eventually achieving strong inhibition of tumor progression. Moreover, ssPPE_Lap@Fe-TA elicites a robust systemic antitumor immune response by promoting dendritic cells (DCs) maturation and T cell infiltration, and synergizes with anti-PD-L1 antibody (a-PD-L1) to strikingly suppress 4T1 tumor growth and lung metastasis.     

Hijacking Endogenous Iron and GSH Via a Polyvalent Ferroptosis Agonist to Enhance Tumor Immunotherapy

The clinical application of ferroptosis, characterized by iron-dependent lipid peroxidation, is limited because of the serious side effects of using toxic-dose iron. Herein, a polyvalent ferroptosis agonist-a hypoxia responsive polymer bearing 18-crown-6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer-chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH₂) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti-tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8⁺ T-cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer-hijacking endogenous iron and GSH may offer new therapeutic opportunities.     

Ferroptosis-Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Hypertrophic scarring, an abnormal fibroproliferative wound-healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron-dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self-assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework-8 (ZIF-8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF-8 composites exhibit good biocompatibility and pH responsive-degradation inside myofibroblasts. The ZIF-8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti-scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF-8-loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis-mediated strategy for treating fibrotic skin diseases in future clinical application.     

A Bionanozyme with Ultrahigh Activity Enables Spatiotemporally Controlled Reactive Oxygen Species Generation for Cancer Therapy

Nanozymes hold great potential in nanomedicine, yet biotoxicity limits their clinical translation because of their uncontrolled catalytic activity, artificial inorganic components, and harsh synthesis conditions. Herein, a peroxidase-like bionanozyme with ultrahigh and photocontrolled catalytic activity through the self-assembly of biomolecules, hemin, and in situ polymerization of pyrrole in an aqueous solution is reported. Such bionanozymes leverage the specific cues of the tumor microenvironment and precise light-induced photothermal heating for spatiotemporally controlled reactive oxygen species generation in tumors. The tunable catalytic activity and excellent biocompatibility of the bionanozyme result in high cancer cell apoptosis and tumor growth inhibition in murine models with negligible biotoxicity. This work highlights the potential of biomolecule-based nanozymes for cancer-specific therapy. Bionanozymes with ultrahigh and tunable catalytic activity may lay the important foundation for more advanced nanomedicine and biosensing.     

Targeted Magnetic Resonance Imaging/Near-Infrared Dual-Modal Imaging and Ferroptosis/Starvation Therapy of Gastric Cancer with Peritoneal Metastasis

Accurate identification and visualization of peritoneal metastases (PM) are clinically essential to improving the prognosis for gastric cancer. However, owing to the multifocal spread of peritoneal metastasis nodules, small size, and close contact with adjacent organs, identifying and completely removing them during surgery is extremely challenging, resulting in cancer treatment failure and recurrence. This study develops a T₁-weighted magnetic resonance imaging (MRI) contrast agent (FeGdNP)-loaded indocyanine green/glucose oxidase (ICG/GOx) with conjugation of an RGD dimer (RGD2) and acid-labile polymer mPEG (FeGdNP-ICG/GOx-RGD2-mPEG). Compared with commercial Magnevist, the proposed FeGdNP-ICG/GOx-RGD2-mPEG shows a two to three-fold higher tumor ΔSNR in MRI of peritoneal metastasis and subcutaneous animal models. Compared with free ICG, the increased fluorescent signal of FeGdNP-ICG/GOx-RGD2-mPEG allows for the detection of tiny tumor metastatic nodules (<3 mm), and the removal of the peritoneum transplanted tumors. Abundant gluconic acid and H₂O₂ are generated during the GOx-mediated glucose depletion process in cancer cells, thereby enhancing Fenton reaction efficiency. Accumulated toxic ·OH can damage the mitochondrial function and induce the release of mitochondrial reactive oxygen species, which activates the ferroptosis pathway. The data indicate the potential of the nanoparticles for MRI preoperative diagnosis, intraoperative fluorescence-guided navigation, and ferroptosis tumor therapy.     

GSH-Responsive Radiosensitizers with Deep Penetration Ability for Multimodal Imaging-Guided Synergistic Radio-Chemodynamic Cancer Therapy

Radiotherapy (RT) utilizes the non-invasive and high penetration X-ray as the energy source to eliminate deep-seated tumors. The efficacy of RT can be optimized by designing effective radiosensitizers and synergizing with other treatment methods. Glutathione (GSH)-responsive radio-sensitizing nanovesicles are designed with size-transformability via self-assembly of gold-manganese oxide Janus nanoparticles (JNPs) encapsulating the near-infrared fluorescence (NIR) dye (IR1061). In the presence of GSH, JNP vesicles (Ves) dissociate into smaller gold (Au) NPs and manganese ion (Mn²⁺) that not only penetrate into the deeper layers of the tumor but also deplete the GSH and trigger chemodynamic therapy (CDT) through a Fenton-like reaction, which augments the efficacy of RT. In addition, the IR1061 released from the disintegrated nanostructures fluoresces in the NIR-II window, and along with photoacoustic (PA) and magnetic resonance imaging (MRI) enables high precision tumor detection. The combination of JNP Ve and X-ray irradiation achieves multimodal image-guided ablation of subcutaneous as well as deep-seated tumors in murine models. Therefore, this novel multimodal image-guided RT/CDT therapeutic platform is a promising strategy in high-precision tumor therapy.     

Microneedle Patch Integrated with Porous Silicon Confined Dual Nanozymes for Synergistic and Hyperthermia-Enhanced Nanocatalytic Ferroptosis Treatment of Melanoma

Superficial melanoma is the deadliest form of skin cancer without desirable clinically therapeutic options. Nanozymes, artificial nanomaterials with physicochemical performance and enzyme catalytic properties, have attracted considerable attention for antitumor therapy. However, the therapeutic efficiency of nanozymes is vulnerable to the tumor microenvironment (TME) and delivery process. Herein, a microneedle (MN) patch that integrates porous silicon (PSi) loaded with dual nanozymes is devised to bidirectionally regulate TME and accurately deliver nanocomplex to initiate ferroptosis for melanoma treatment. Benefitting from the channel confinement effect of PSi, the copper-doped graphene quantum dots and palladium nanoparticles coloaded PSi (CuGQD/PdNPs@PSi) exhibit synergistic effect with enhanced mimicking peroxidase and glutathione oxidase activities, which are ≈2–3-fold higher than those of monoconfined nanozyme or nonconfined nanozyme complexes. Additionally, the synergistic catalytic performance of CuGQD/PdNPs@PSi can be improved via photostimuli hyperthermia. The CuGQD/PdNPs@PSi can induce ferroptosis manifested by upregulation of lipid peroxides and inactivation of glutathione peroxidase 4. Furthermore, loading of nanocomplexes into MNs for administration resulted in a satisfactory melanoma growth inhibition of 98.8% within 14 days. Therefore, MNs encapsulated with CuGQD/PdNPs@PSi can provide a potentially nanocatalytic strategy for ferroptosis-inducing tumor treatment while also meeting the medical needs of eradicating superficial tumors.     

Hypoxia-Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

The immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia-responsive delivery system is constructed simply by coordinating ferric (Fe³⁺) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia-sensitive dopamine derivative of polyethylene glycol (PEG) using “one-pot” reaction for the “closed-loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia-sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate-cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8⁺ T cells then release interferon γ (IFN-γ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed-loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor-bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.     

Co‐delivery of Cell‐permeable Chimeric Apoptosis AVPIR8 Peptide/p53 DNA for Cocktail Therapy

The tetra‐peptide AVPI, derived from the Smac/DIABLO N‐terminal epitope, is able to trigger caspase activation and apoptotic process. However, its clinical value is greatly hampered by the nature of membrane‐impermeability. Herein, the cell‐penetrating chimeric apoptotic peptide of AVPIR₈ is synthesized, of which the apoptosis‐induced AVPI is strategically blended with the cell‐penetrating sequence of octaarginine (R₈). The dual‐functionalized AVPIR₈ is not only potent in inducing apoptosis in tumor cells due to the cell penetration ability, but also is able to work as gene carrier for transfering the tumor suppressor p53 DNA into cells, thus constructing a co‐delivery drug system (AVPIR₈/p53). Such system efficiently promotes apoptosis in cancer cells while sparing normal cells, and its antitumor activity is further significantly enhanced in combination with doxorubicin as cocktail therapy. More importantly, the anticancer efficacy of the cocktail is demonstrated to be able to arrest tumor growth in two animal tumor models (melanoma and cervical cancers), respectively. The chemotherapeutic dose in the AVPIR₈/p53‐based cocktail is significantly reduced by 80%, compared to the monotherapy of doxorubicin. The present results show the promise of the co‐delivered AVPIR₈/p53 as adjuvant therapy for boosting the conventional chemotherapeutics, with a unique benefit of enhanced productive treatment outcomes yet greatly reduced adverse toxicity.     

A Microenvironment Dual-Responsive Nano-Drug Equipped with PD-L1 Blocking Peptide Triggers Immunogenic Pyroptosis for Prostate Cancer Self-Synergistic Immunotherapy

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM-1 cells and successfully induce an apoptosis-pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual-responsive nano-drug equipped with PD-L1 blocking peptide (TSD@LSN-D) is developed for self-synergistic cancer immunotherapy. The poorly immunogenic RM-1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN-D not only can effectively inhibit the primary tumor but also form a long-term immune memory to prevent PCa recurrence and metastasis. To the best of authors’ knowledge, this work presents the first concept that promotes the apoptosis–pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy.     

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.     

Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

Spatiotemporal Theranostic Nanoprobes Dynamically Monitor Targeted Tumor Therapy

Currently, spatiotemporal theranostic nanoprobes are in great demand, owing to their enhanced target therapy and precise dynamic tracing of in vivo drug fate. Herein, this study highlights the successful development of dynamic theranostic nanoprobes, which are facilely established via self-assembly between glutathione (GSH)-responsive dasatinib (DAS) dimers and indocyanine green (ICG). The DAS dimers endow the nanoprobes with aggregation-induced emission (AIE) characteristic, whose emission wavelength successfully redshifts from 420 to 810 nm compared to DAS-based nanoprobes, the same as that of ICG, thus improving the total fluorescence intensity. Moreover, the nanoprobes exhibit a dynamic fluorescence intensity conversion that first decreases and then increases at the tumor site via intracellular GSH-triggered AIE quenching and fluorescence re-enhancement of ICG, therefore achieving precise tumor diagnosis, prognosis evaluation, and spatiotemporal tracing of drug fate compared to other imaging strategies. Furthermore, the nanoprobes show long-term circulation stability via suitable particle sizes and zeta potentials, improved tumor accumulation via extracellular protonation and active cellular uptake, efficient drug release via response to the intracellular milieu, and enhanced apoptosis via targeting to intracellular kinase, therefore achieving the significant tumor inhibition. Thus, the spatiotemporal theranostic nanoprobes can dynamically monitor the targeted tumor therapy, greatly advancing their application in clinics.