Antithrombotic Therapy by Regulating the ROS-Mediated Thrombosis Microenvironment and Specific Nonpharmaceutical Thrombolysis Using Prussian Blue Nanodroplets.

In thrombotic diseases, the effects of reactive oxygen species (ROS)-mediated oxidative stress as a "perpetrator" in thrombosis must be resolved. Accordingly, an insufficient understanding of thrombus therapy prompted the authors to pursue a more comprehensive and efficient antithrombotic treatment strategy. A Prussian blue (PB)-based nanodroplet system (PB-PFP@PC) is designed using PB and perfluorinated pentane (PFP) in the core, and a targeting peptide (CREKA, Cys-Arg-Glu-Lys-Ala) is attached to poly(lactic-coglycolic acid) (PLGA) as the delivery carrier shell. Upon near-infrared (NIR) laser irradiation, PB and PFP jointly achieve an unprecedented dual strategy for drug-free thrombolysis: photothermal therapy (PTT) combined with optical droplet vaporization (ODV). PB, a nanoenzyme, also regulates the vascular microenvironment via its antioxidant activity to continuously scavenge abnormally elevated ROS and correspondingly reduce inflammatory factors in the thrombus site. This study provides a demonstration of not only the potential of ODV in thrombus therapy but also the mechanism underlying PTT thrombolysis due to thermal ablation-induced fibrin network structural damage. Moreover, PB catalyzes ROS to generate oxygen (O2 ), which combines with the ODV effect, enhancing the ultrasound signal. Thus, regulation of the thrombosis microenvironment combined with specific nonpharmaceutical thrombolysis by PB nanodroplets provides a more comprehensive and efficient antithrombotic therapeutic strategy.

Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer.

BACKGROUND: Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. RESULTS: Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated "M@P-PDR"), which acted as "Nano-targeted cells" to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with "Nano-targeted cells"-based cocktail therapy. CONCLUSION: "Nano-targeted cells"-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence.

Multifunctional ICG-SB@Lip-ZA Nanosystem Focuses on Remodeling the Inflammatory-Immunosuppressive Microenvironment After Photothermal Therapy to Potentiate Cancer Photothermal Immunotherapy.

Achieving full eradication of residual tumors post photothermal therapy (PTT) hinges on the immune system's activation and response. Nevertheless, the resultant local inflammation attracts a significant influx of aberrant immune cells and fibroblasts, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), following tumor PTT. This phenomenon exacerbates immune evasion and the persistence of residual tumor cells, culminating in tumor recurrence and advancement. To tackle this challenge, a combined therapeutic approach utilizing multifunctional ICG-SB@Lip-ZA nanosystem has been introduced. Indocyanine green (ICG) as a photothermal-transducer ablated tumor cells, zoledronic acid (ZA) depletes TAMs recruited by the inflammatory tumor microenvironment (mostly M2-like phenotype), SB-505124 affects CAFs proliferation in the tumor microenvironment (TME) by inhibiting the transforming growth factor-ß ï¼ˆTGF-ß） pathway, thereby removing physical barriers to T cell infiltration. In a breast cancer model, these immunomodulatory nanoliposomes markedly decrease the population of M2-like TAMs in the TME, eliminate physical barriers hindering T cell infiltration, reshape the inflammatory immune-suppressive tumor microenvironment, eventually leading to a rate of tumor eradication of 94%. This multifunctional ICG-SB@Lip-ZA nanosystem (including photothermal conversion, TAM depletion, and TGF-ß pathway blockade) offers a promising strategy for mitigating the deteriorating tumor microenvironment following PTT and presents a more efficient approach for clinical photothermal-immune combination therapy.

Combination of MHI148 Targeted Photodynamic Therapy and STING Activation Inhibits Tumor Metastasis and Recurrence.

Metastasis and recurrence are notable contributors to mortality associated with breast cancer. Although immunotherapy has shown promise in mitigating these risks after conventional treatments, its effectiveness remains constrained by significant challenges, such as impaired antigen presentation by dendritic cells (DCs) and inadequate T cell infiltration into tumor tissues. To address these limitations, we developed a multifunctional nanoparticle platform, termed GM@P, which consisted of a hydrophobic shell encapsulating the photosensitizer MHI148 and a hydrophilic core containing the STING agonist 2'3'-cGAMP. This design elicited robust type I interferon responses to activate antitumor immunity. The GM@P nanoparticles loaded with MHI148 specifically targeted breast cancer cells. Upon exposure to 808 nm laser irradiation, the MHI148-loaded nanoparticles produced toxic reactive oxygen species (ROS) to eradicate tumor cells through photodynamic therapy (PDT). Notably, PDT stimulated immunogenic cell death (ICD) to foster the potency of antitumor immune responses. Furthermore, the superior photoacoustic imaging (PAI) capabilities of MHI148 enabled the simultaneous visualization of diagnostic and therapeutic procedures. Collectively, our findings uncovered that the combination of PDT and STING activation facilitated a more conducive immune microenvironment, characterized by enhanced DC maturation, infiltration of CD8+ T cells, and proinflammatory cytokine release. This strategy stimulated local immune responses to augment systemic antitumor effects, offering a promising approach to suppress tumor growth, inhibit metastasis, and prevent recurrence.

Study on the influence of industrial intelligence on carbon emission efficiency-empirical analysis of China's Yangtze River Economic Belt.

How to achieve the goal of "carbon peak and carbon neutrality" and explore the compatibility of industrial and ecological civilization is a major challenge for China today. This study analyzes the impact of industrial intelligence on industrial carbon emissions efficiency in 11 provinces of China's Yangtze River Economic Belt, measuring the efficiency of industrial carbon emissions through the non-expected output slacks-based measure (SBM) model, selecting industrial robot penetration to measure the level of industrial intelligence, establishing a two-way fixed model to verify the impact of industrial intelligence on carbon emission efficiency, and testing for intermediary effects and regional heterogeneity. The results show that: (1) the industrial carbon emission efficiency of the 11 provinces shows year-over-year improvement, with significant differences between upstream, midstream, and downstream, where downstream is the highest and upstream is the lowest. (2) The development of industrial intelligence is highly uneven, with the upstream level being the weakest. (3) Industrial intelligence can improve the efficiency of industrial carbon emissions by enhancing green technological innovation and energy use efficiency. (4) The effect of industrial intelligence on industrial carbon emission efficiency also shows regional heterogeneity. Finally, we present policy recommendations. This research provides mathematical and scientific support for achieving carbon reduction targets at an early stage and helps accelerate the construction of a modern, low-carbon China.

Tumor microenvironment remodeling via targeted depletion of M2-like tumor-associated macrophages for cancer immunotherapy.

M2-like tumor-associated macrophages (TAMs) typically exhibit numerous tumor-promoting properties. Reducing the abundance of M2-like TAMs would shed light on the relief of immunosuppressive tumor microenvironment (TME), activation of the host immune system, infiltration of CD8+ T cells into the TME and restoring the function of the infiltrating T cells, which collectively inhibits tumor growth. Therefore, targeted depletion of M2-like TAMs can be a promising immunotherapy approach. In this study, we rationally constructed an M2-like TAMs-targeted nanoliposome, which encapsulates zoledronic acid (ZA) in the core, loads hematoporphyrin monomethyl ether (HMME, a typical sonosensitizer) in the lipid bilayer, and modifies M2pep peptide (the targeting unit) on the surface (designated as M-H@lip-ZA). Our aim is to validate the effectiveness of M-H@lip-ZA nanoliposomes to remodel TME via targeted depletion of M2-like TAMs for cancer immunotherapy. Through the M2pep peptide, M-H@lip-ZA can be efficiently delivered to M2-like TAMs. In the meantime, reactive oxygen species (ROS) resulting from sonodynamic therapy (SDT), together with inner ZA that shows high affinity and cytotoxicity to TAMs, can effectively deplete M2-like TAMs and remodel TME (normalize tumor vasculatures, strengthen intertumoral perfusion, ease tumor hypoxia, increase immune-promoting cytokines and decrease immunosuppressive cytokines). The tumor growth can be effectively inhibited. This work proposed a new paradigm for cancer immunotherapy via targeted depletion of M2-like TAMs. STATEMENT OF SIGNIFICANCE: • M2-like TAMs-targeted nanoliposome (M-H@lip-ZA) was designed and prepared. • Sonodynamic therapy (SDT), together with zoledronic acid (ZA) that shows high affinity and cytotoxicity to tumor-associated macrophages (TAMs), can effectively deplete M2-like TAMs. Subsequently, immune-promoting tumor microenvironment (TME) can be formed, which includes normalized tumor vasculatures, enhanced intertumoral perfusion, relieved tumor hypoxia, increased immune-promoting cytokines, and decreased immunosuppressive cytokines. • The targeted depletion of M2-like TAMs is a promising cancer immunotherapy approach.

Novel combination strategy of high intensity focused ultrasound (HIFU) and checkpoint blockade boosted by bioinspired and oxygen-supplied nanoprobe for multimodal imaging-guided cancer therapy.

BACKGROUND: High-intensity focused ultrasound (HIFU) has shown considerable promise in treating solid tumors, but its ultrasonic energy is easily attenuated, resulting in insufficient energy accumulation in the target area. Moreover, HIFU ablation alone may inevitably lead to the presence of residual tumors, which may cause tumor recurrence and metastasis. Here, we describe a synergistic regimen combining HIFU facilitation with immunomodulation based on a novel oxygen-carrying biomimetic perfluorocarbon nanoparticle (M@P-SOP) to stimulate immunogenic cell death in tumor cells while alleviating immune suppression tumor microenvironment. METHODS: M@P-SOP was prepared by double emulsion and film extrusion method. The anticancer and antimetastatic effects of M@P-SOP were evaluated on a preclinical transplanted 4T1 tumor model by combining HIFU and immunotherapy. Flow cytometry and immunofluorescence were used to clarify the potential mechanism of HIFU+M@P-SOP and their role in anti-programmed death ligand-1 (PD-L1) therapy. RESULTS: Guided by photoacoustic/MR/ultrasound (US) multimodal imaging, M@P-SOP was abundantly enriched in tumor, which greatly enhanced HIFU's killing of tumor tissue in situ, induced stronger tumor immunogenic cell death, stimulated dendritic cell maturation and activated CD8+ T cells. At the same time, M@P-SOP released oxygen to alleviate the tumor hypoxic environment, repolarizing the protumor M2-type macrophages into antitumor M1-type. With concurrent anti-PD-L1 treatment, the antitumor immune response was further amplified to the whole body, and the growth of mimic distant tumor was effectively suppressed. CONCLUSIONS: Our findings offer a highly promising HIFU synergist for effectively ameliorating acoustic and hypoxia environment, eventually inhibiting tumor growth and metastasis by stimulating host's antitumor immunity under HIFU ablation, especially in synergizing with PD-L1 antibody immunotherapy.

Biomimetic "Nanoplatelets" as a Targeted Drug Delivery Platform for Breast Cancer Theranostics.

Breast cancer is a major threat to health and lives of females. Biomimetic nanotechnology brought brighter hope for early diagnosis and treatment of breast cancer. Here, we proposed a platelet (PLT) membrane-derived strategy for enhanced photoacoustic (PA)/ultrasonic (US)/fluorescence (FL) multimodal imaging and augmented synergistic photothermal/chemotherapeutic efficacy in tumor cells. A PA imaging contrast and photothermal agent, nanocarbons (CNs), a chemotherapeutic and FL material, doxorubicin (DOX), and perfluoropentane (PFP) were coencapsulated into the poly(lactic-co-glycolic) acid (PLGA) skeletons. Then, the PLT membranes were coated onto the PLGA NPs, which were named as "nanoplatelets" (DOX-PFP-CNs@PLGA/PM NPs). The "nanoplatelets", which conserved the structural advantages and inherent properties of PLTs, could not only escape from phagocytosis of macrophages but also actively targeted tumor cells by the way of antigen-antibody interactions between P-selectin on the PM and CD44 receptors of the tumor cells. With CNs and DOX loaded in, these "nanoplatelets" could serve as an excellent contrast agent for PA/FL imaging. Under laser irradiation, the "nanoplatelets" could turn light energy into heat energy. The laser-triggered photothermal effect, on the one hand, could ablate the tumor cells immediately, and on the other hand, could initiate the optical droplet vaporization of PFP, which subsequently enhanced US imaging and promoted the discharge of encapsulated DOX from the "nanoplatelets" for remarkably strengthening photothermal therapeutic power in turn. In this work, as compared with the bare drug-loaded nanoparticles, the "nanoplatelets" exhibited much more accumulation in the tumor cells, demonstrating superior multimodal imaging capability and preferable synergistic therapeutic performance. In conclusion, the "nanoplatelets" could serve as contrast agents for US imaging and PA imaging to guide the therapy. What is more, the bioinspired PLT-derived, targeted, and nontoxic "nanoplatelets", which were exploited for multimodal PA/US/FL imaging-guided synergistic photothermal/chemo therapy, will be of great value to breast cancer theranostics in the days to come.

Nanomedicine Enables Drug-Potency Activation with Tumor Sensitivity and Hyperthermia Synergy in the Second Near-Infrared Biowindow.

Disulfiram (DSF), a U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism, is also used as an antitumor drug in combination with Cu2+ ions. However, studies have shown that the endogenous Cu2+ dose in tumor tissues is still insufficient to form relatively high levels of a bis(N,N-diethyldithiocarbamate) copper(II) complex (denoted as Cu(DTC)2) to selectively eradicate cancer cells. Here, DSF-loaded hollow copper sulfide nanoparticles (DSF@PEG-HCuSNPs) were designed to achieve tumor microenvironment (TME)-activated in situ formation of cytotoxic Cu(DTC)2 for NIR-II-induced, photonic hyperthermia-enhanced, and DSF-initiated cancer chemotherapy. The acidic TME triggered the gradual degradation of DSF@PEG-HCuSNPs, promoting the rapid release of DSF and Cu2+ ions, causing the in situ formation of cytotoxic Cu(DTC)2, to achieve efficient DSF-based chemotherapy. Additionally, DSF@PEG-HCuSNPs exhibited a notably high photothermal conversion efficiency of 23.8% at the second near-infrared (NIR-II) biowindow, thus significantly inducing photonic hyperthermia to eliminate cancer cells. Both in vitro and in vivo studies confirmed the effective photonic hyperthermia-induced chemotherapeutic efficacy of DSF by integrating the in situ formation of toxic Cu(DTC)2 complexes and evident temperature elevation upon NIR-II laser irradiation. Thus, this study represents a distinctive paradigm of in situ Cu2+ chelation-initiated "nontoxicity-to-toxicity" transformation for photonic hyperthermia-augmented DSF-based cancer chemotherapy.

Multifunctional nanozyme for multimodal imaging-guided enhanced sonodynamic therapy by regulating the tumor microenvironment.

Sonodynamic therapy (SDT) is a highly promising approach for cancer therapy, but its efficacy is severely hampered by the low specificity of sonosensitizers and the unfavorable characteristics of the tumor microenvironment (TME), such as hypoxia and glutathione (GSH) overexpression. To solve these problems, in this work, we encapsulated IR780 and MnO2 in PLGA and linked Angiopep-2 (Ang) to synthesize a multifunctional nanozyme (Ang-IR780-MnO2-PLGA, AIMP) to enhance SDT. With Ang functionalization to facilitate blood-brain barrier (BBB) penetration and glioma targeting, and through the function of IR780, these nanoparticles (NPs) showed improved targeting of cancer cells, especially mitochondria, and spread deep into tumor centers. Upon low-intensity focused ultrasound (LIFU) irradiation, reactive oxygen species (ROS) were produced and induced tumor cell apoptosis. Combined with the specific mitochondria-targeting ability of IR780, the sonodynamic effects were amplified because mitochondria are sensitive to ROS. In addition, MnO2 exhibited enzyme-like activity, reacting with the high levels of hydrogen protons (H+), H2O2 and GSH in the TME to continuously produce oxygen and consume GSH, which further enhanced the effect of SDT. Moreover, Mn2+ can be released in response to TME stimulation and used as a magnetic resonance (MR) contrast agent. In addition, IR780 has photoacoustic (PA)/fluorescence (FL) imaging capabilities. Our results demonstrated that AIMP NPs subjected to LIFU triggering maximally enhanced the therapeutic effect of SDT by multiple mechanisms, including multiple targeting, deep penetration, oxygen supply in situ and GSH depletion, thereby significantly inhibiting tumor growth and distal metastasis without systemic toxicity. In summary, this multifunctional nanozyme provides a promising strategy for cancer diagnosis and treatment under the intelligent guidance of multimodal imaging (PA/FL/MR) and may be a safe clinical translational method.

Light-Responsive Core-Shell Nanoplatform for Bimodal Imaging-Guided Photothermal Therapy-Primed Cancer Immunotherapy.

Photothermal therapy (PTT) as a noninvasive and effective thermal therapeutic approach has attracted tremendously increasing interest because it can effectively eliminate the primary tumor and generate tumor-associated antigens, which could elicit antitumor immune responses. Herein, we report on the rational design and fabrication of copper sulfide (CuS)-based nanoplatform for cancer photothermal immunotherapy. The as-prepared core-shell CuS@mSiO2-PFP-PEG (CPPs) nanocomposites possess high biocompatibility, photoacoustic (PA)/ultrasound (US) imaging, and strong PTT effect upon 808 nm laser irradiation, indicating that the nanocomposites have a promising application in diagnosis and treatment of breast cancer with molecular classification. Importantly, we also elucidated that the CPP-triggered PTT in combination with anti-PD-1 checkpoint blockade therapy can not only obliterate primary tumor but also inhibit metastatic tumor in tumor-bearing mice. We believe that the CPPs have a good probability to serve as a useful nanoplatform for PTT, and this approach may provide a promising strategy for tumor-therapeutic modality with immunotherapy.

Dual ultrasound-activatable nanodroplets for highly-penetrative and efficient ovarian cancer theranostics.

The selective delivery and deep intertumoral penetration of nanosensitizers remain challenging in the fabrication of sonodynamic therapy (SDT) platforms. In this work, we rationally constructed dual ultrasound (US)-activatable nanodroplets (NDs)/nanoliposomes/nanosensitizers with perfluoropentane (PFP) in the core, hematoporphyrin monomethyl ether (HMME) in the phospholipid shell and folate (FA)-conjugated to the surface (collectively termed FA-H@NDs). We aimed to validate the feasibility of these FA-H@NDs for FA receptor (FR)-overexpressed ovarian cancer theranostics. The ND formulations were based on PFP that can undergo acoustic droplet vaporization (ADV) when exposed to US irradiation. The ADV phenomenon disrupts the adjacent vasculature, and the resistance to drug diffusion within the tumor can be decreased, enabling nanosensitizers to more deeply penetrate into the inner tissue far from the intertumoral vasculature. These FA-H@NDs assisted by US irradiation can also induce the production of excess reactive oxygen species (ROS) and consequently trigger tumor cell/tissue apoptosis and necrosis. Furthermore, this therapeutic process can be guided and monitored by US/photoacoustic (PA) dual-modal imaging. This work established a new paradigm for highly efficient ovarian cancer theranostics based on the rational utilization of dual US-activatable NDs.