Tumor Microenvironment‐Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy

Advanced Materials, Год журнала: 2023, Номер 36(6)

Опубликована: Сен. 19, 2023

Abstract Insufficient activation of the stimulator interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits effect cancer immunotherapy. Herein, tumor (TME)‐responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING Toll‐like receptor 4 (TLR4) to augment via TLR4‐mediated nuclear factor‐kappa B stimulation, leading increased secretion type I interferons (i.e., 4.0‐fold enhancement IFN‐β) pro‐inflammatory cytokines promote a specific T cell immune response. Moreover, PMM NPs relieve immunosuppression TME by decreasing percentage regulatory cells, polarizing M2 macrophages M1 type, thus creating an immune‐supportive unleash cascade adaptive Combined with anti‐PD‐1 antibody, synergistic efficacy is achieved in both inflamed colorectal noninflamed metastatic breast models. rechallenging tumor‐free animals homotypic cells induced complete rejection, indicating generation systemic antitumor memory. These TME‐responsive may open new avenue achieve spatiotemporal orchestration activation, providing promising clinical candidate for next‐generation

Язык: Английский

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Bioactivable STING Nanoagonists to Synergize NIR‐II Mild Photothermal Therapy Primed Robust and Long‐Term Anticancer Immunity

Advanced Materials, Год журнала: 2023, Номер 35(48)

Опубликована: Сен. 11, 2023

Pharmacological activation of the stimulator interferon genes (STING) pathway has become a promising strategy for cancer immunotherapy. However, insufficient tumorous accumulation, rapid clearance, and short duration drug efficacy in tumor microenvironment small structural STING agonists greatly compromise therapeutic efficacy. Herein, extracellular matrix (ECM) is presented anchoring agonist-based photoimmunothernostic nanomedicine (SAPTN) that can be activated by mild-temperature photothermal therapy (mild PTT) induced neutrophilic inflammation. The SAPTN owns second window near-infrared (NIR-II) photonics properties fitting NIR-II fluorescence photoacoustic imaging-guided therapy. aggregates targeting to ECM provide slow continuous release potent diABZIs. mild PTT long-lasting released synergistically prime systematic, robust, long-term anticancer immunity. In model, this approach leads complete eradication about 100% mice with orthotopic breast tumors, regained tumor-free survival at least 2 months. addition, immune-mediated abscopal effect shows inhibition distant solid growth intratumoral administration laser irradiation. Overall, represents generalized photoactivable immunity improved theranostics.

Язык: Английский

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A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy

Biomaterials, Год журнала: 2023, Номер 302, С. 122300 - 122300

Опубликована: Авг. 29, 2023

Язык: Английский

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A Hybrid Nanoadjuvant Simultaneously Depresses PD‐L1/TGF‐β1 and Activates cGAS‐STING Pathway to Overcome Radio‐Immunotherapy Resistance

Advanced Materials, Год журнала: 2024, Номер 36(15)

Опубликована: Янв. 17, 2024

Abstract Currently, certain cancer patients exhibit resistance to radiotherapy due reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor‐β1 (TGF‐β1) membrane‐localized programmed death ligand‐1 (PD‐L1). Meanwhile, cytoplasm‐distributed PD‐L1 induces through accelerating repair (DDR). However, the disability of clinically used antibodies in inhibiting limits their effectiveness. Therefore, a nanoadjuvant is developed sensitize via multi‐level immunity activation depressing TGF‐β1 triphenylphosphine‐derived metformin, activating cGAS‐STING pathway generating Mn 2+ from MnO 2 producing more dsDNA reversing tumor hypoxia impairing DDR. Thus, Tpp‐Met@MnO @Alb effectively enhances efficiency inhibit progression irradiated local abscopal tumors lung metastases, offering long‐term memory antitumor without discernible side effects. Overall, has potential be applied for overcoming radio‐immunotherapy resistance.

Язык: Английский

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Decomposable Nanoagonists Enable NIR‐Elicited cGAS‐STING Activation for Tandem‐Amplified Photodynamic‐Metalloimmunotherapy

Advanced Materials, Год журнала: 2024, Номер 36(21)

Опубликована: Фев. 14, 2024

Activation of the cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve therapeutic outcomes immunotherapy. However, "constantly active" mode current STING agonist delivery strategies typically leads off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized activation photodynamic-metalloimmunotherapy. The engineered enabled generation mitochondria-targeted reactive oxygen species under NIR irradiation specifically release mitochondrial DNA (mtDNA) inhibit repair nuclear via hypoxia-responsive drugs. Oxidized tumor mtDNA serves endogenous danger-associated molecular pattern that activates cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance cGAS enzymatic activity through metalloimmune effects. By combining synergistically enhanced triggered by irradiation, facilitated maturation dendritic infiltration cytotoxic T lymphocytes primary eradication, which also established long-term anti-tumor immunity suppress metastasis. Therefore, developed NIR-triggered, agonist-free, tandem-amplified pathway, thereby offering distinct paradigm

Язык: Английский

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Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Янв. 7, 2024

Abstract The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing crucial role in improving antitumor immunity through effector responses. Targeting the holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective elimination. However, systemic administration current STING agonists faces challenges related to low bioavailability potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed modulate TMEs robust immunotherapeutic encapsulation delivery within nanoparticles (STING-NPs) present an attractive avenue immunotherapy. This review explores range designed encapsulate agonists, highlighting benefits, including favorable biocompatibility, improved penetration, efficient intracellular agonists. also summarizes immunomodulatory impacts STING-NPs on TME, enhanced secretion pro-inflammatory cytokines chemokines, dendritic cell activation, cytotoxic T priming, macrophage re-education, vasculature normalization. Furthermore, offers insights into co-delivered nanoplatforms involving alongside agents such chemotherapeutic compounds, checkpoint inhibitors, antigen peptides, other adjuvants. These platforms demonstrate remarkable versatility inducing immunogenic responses ultimately amplifying

Язык: Английский

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Engineered nanoparticles for precise targeted drug delivery and enhanced therapeutic efficacy in cancer immunotherapy

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(8), С. 3432 - 3456

Опубликована: Май 13, 2024

The advent of cancer immunotherapy has imparted a transformative impact on treatment paradigms by harnessing the power immune system. However, challenge practical and precise targeting malignant cells persists. To address this, engineered nanoparticles (NPs) have emerged as promising solution for enhancing targeted drug delivery in immunotherapeutic interventions, owing to their small size, low immunogenicity, ease surface modification. This comprehensive review delves into contemporary research at nexus NP engineering immunotherapy, encompassing an extensive spectrum morphologies strategies tailored toward optimizing tumor augmenting therapeutic effectiveness. Moreover, it underscores mechanisms that NPs leverage bypass numerous obstacles encountered regimens probes combined potential when co-administered with both established novel modalities. Finally, evaluates existing limitations platforms which could shape path future advancements this field.

Язык: Английский

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Metal‐Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(12)

Опубликована: Фев. 2, 2024

Abstract Due to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet cell vaccines require multi‐step production that frequently leads loss immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole‐cell cancer vaccine by cloaking with lipopolysaccharide‐decorated manganese(II)‐phenolic networks (MnTA nanocloaks) evoke tumor‐specific response for highly efficacious synergistic immunotherapy. The polyphenols coordinate Mn 2+ immediately adhere surface individual cells, thereby forming nanocloak encapsulating neoantigens. Subsequent decoration lipopolysaccharide induces internalization dendritic where ions are released in cytosol, further facilitating stimulator interferon genes (STING) pathway. Highly effective suppression was observed combining nanocloaked treatment anti‐programmed death ligand 1 (anti‐PD‐L1) antibodies‐mediated checkpoint blockade therapy. Our work demonstrates universal yet simple strategy engineer cell‐based nanobiohybrid system enhanced

Язык: Английский

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Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 22, 2024

Abstract Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance toxicity still remain. Due the advancement of immuno-oncology, an increasing number novel immunoregulatory targets mechanisms are being revealed, with relevant therapies promising improve clinical immunotherapy in foreseeable future. Therefore, comprehending larger picture is important. In this review, we analyze summarize current landscape preclinical translational mechanistic research, drug development, trials that brought about next-generation pharmacological anti-cancer agents candidates beyond classical immune checkpoint inhibitors. Along further clarification immunobiology advances antibody engineering, targeting additional inhibitory checkpoints, including LAG-3, TIM-3, TIGIT, CD47, B7 family members becoming important part research discovery, as structurally functionally optimized agonists co-stimulatory molecules T cells. Exemplified bispecific cell engagers, newly emerging bi-specific multi-specific antibodies can provide considerable benefits. Next-generation also include epigenetic drugs cytokine-based therapeutics. Cell therapies, vaccines, oncolytic viruses not covered review. This comprehensive review might aid development fastest possible adoption effective immuno-oncology modalities for benefit patients.

Язык: Английский

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Antigen Self-Presented Personalized Nanovaccines Boost the Immunotherapy of Highly Invasive and Metastatic Tumors

ACS Nano, Год журнала: 2024, Номер 18(8), С. 6333 - 6347

Опубликована: Фев. 13, 2024

Dendritic cell (DC)-based vaccines have shown promise in adoptive therapy for enhancing the antigen-specific response of antitumor immunity. However, their clinical efficacy is limited by less-presented tumor-associated antigens (TAAs) through MHC I and low lymph node homing efficiency. Herein, to address these issues, we rationally design fabricate DC-based nanovaccines coating Cu2–xSe nanoparticles (CS NPs) with membrane matured DCs (named as DCNV(CSD) nanovaccines). We reveal important roles CS NPs from three aspects: (1) inducing immunogenic death tumor cells expose abundant TAAs; (2) promoting escape TAAs lysosomes during antigen presenting process I; (3) sustainably releasing traces copper ions promote proliferation T cells. Our are characterized high expressions I, CD80, CD86, CCR7, ICAM-1 proteins, which not only endow them abundantly processed specific TAAs, but also a strong capability nodes. The our small better than that DCs. More importantly, they can elicit potent antispecific CD8+ immunotherapy, tested treatment highly invasive glioblastoma metastatic melanoma. Additionally, generate memory (TEM) spleen mice effectively prevent recurrence treated tumors. This work demonstrates universal approach high-performance immunotherapy using versatile NPs.

Язык: Английский

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