Myocardial ischemia-reperfusion injury (MIRI) triggers innate immunity and excessive inflammation, which could potentially be reversed by shifting the immune system from activation to tolerance. However, conventional immune interventions predominantly aim to suppress local inflammation within the myocardium, and their effectiveness is limited by challenges associated with targeted delivery to and retention within myocardial tissue. To address this, a novel drug delivery system, designated as PBEPR@Man, has been developed to effectively deliver the highly immunogenic myocardial infarction tissue lysates (MITLs) that address the existing challenges related to the low immunogenicity and limited specificity of mono-antigen strategies. This system was specifically engineered to target lymph nodes, with the aim of enhancing lymph nodes dendritic cells (DCs)-driven immune tolerance in situ. PBEPR@Man promoted tolerogenic DCs generation and antigen-specific regulatory T cells (Tregs) proliferation, which synergistically enhanced immunosuppression. Tregs infiltrated into the infarcted area and promoted M2 macrophage polarization, thereby modulating the inflammatory microenvironment. Results demonstrated that PBEPR@Man effectively suppressed excessive inflammatory responses in myocardial tissue and improved cardiac function. This project will provide a theoretical basis for self-antigen-based immunotherapy for the treatment of MIRI.

Rationale: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and persistent inflammation in multiple joints is an important sign for the progression of RA. To this end, we developed the transdermal microneedle integrating biomimetic self-enhancing Fenton reaction nano-reactor, for the purposes of eliminating reactive oxygen species, reducing hypoxia and inflammation, and regulating macrophage phenotype. Methods: A novel biomimetic self-enhanced Fenton reaction nano-reactor was synthesized using an M1 macrophage cell membrane-coated tannic acid-modified iron oxide nanoparticle (IO-NH2-TA TNPs@M1). The regulatory mechanisms of the IO-NH2-TA TNPs@M1 were investigated by evaluating ROS scavenging, degree of hypoxia, adsorption of pro-inflammatory factors, and M2 macrophage polarization. Then, the nano-reactor was incorporated into a dissolving microneedle, utilizing enzyme-cut oligomeric sodium hyaluronate, and subsequently assessed for pharmacodynamics and safety. Results: In vitro mechanisms of IO-NH2-TA TNPs@M1 included eliminating ROS, inhibiting the expression of HIF-1α, decreasing the content of pro-inflammatory factors (IL-6 and TNF-α), and inducing macrophage M2 polarization. Pharmacodynamic and in vitro mechanistic studies showed that IO-NH2-TA TNPs@M1DM maximally alleviated joint swelling and fever, protected joint cartilage, improved the local hypoxia environment and promoted macrophage M2 polarization. Cytotoxicity assays and HE staining showed that IO-NH2-TA TNPs@M1DM displayed good biocompatibility. Conclusions: This study designed and synthesized an innovative biomimetic self-enhancing Fenton reaction nano-reactor, and utilized microneedles for the transdermal delivery, providing a scientific and effective new strategy for the precise treatment of RA.

The transdermal patch is a successful long-acting sustained drug delivery system, but in vivo drug absorption is often limited by low drug loading, release and skin permeability. Therefore, an innovative long-acting trans-dermal drug delivery was developed by synthesizing multifunctional ionic liquids (MILs), that complex interactions among the ionic liquid, drug, polymer and skin were illustrated. When MILs were used, drug loading was increased to 13-to 19-fold, drug release amounts were increased to 12-to 18-fold, and drug permeation amounts were increased to approximately 2-to 11-fold. Notably, the AUC0 ->infinity was increased to a maximum of 3963.98 h mu g mL(-1), compared with the control group (212.09 h mu g mL(-1)), and had good in vitro/in vivo correlations (R2 > 0.95). ATR-FTIR and XPS revealed that MILs formed hydrogen and ionic hydrogen bonds between pressure-sensitive adhesive (PSA) and drug, which improved drug loading. MILs affected the thermodynamic properties and increased the mobility of PSA, thus facilitating drug release, which was shown by DSC. ATR-FTIR, DSC, CLSM, and SEM showed that MILs strongly interacted with lipids and keratins in the stratum corneum and interfered with stabilization of lipid bilayer, thereby facilitating skin penetration. The safety of optimized MIL was shown by cytotoxicity, apoptosis, histological experiments, and immunohistochemistry. This study provides a new and simple strategy for developing long-acting transdermal drug delivery utilizing MILs.

Rationale: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and persistent inflammation in multiple joints is an important sign for the progression of RA. To this end, we developed the transdermal microneedle integrating biomimetic self-enhancing Fenton reaction nano-reactor, for the purposes of eliminating reactive oxygen species, reducing hypoxia and inflammation, and regulating macrophage phenotype. Methods: A novel biomimetic self-enhanced Fenton reaction nano-reactor was synthesized using an M1 macrophage cell membrane-coated tannic acid-modified iron oxide nanoparticle (IO-NH2-TA 2-TA TNPs@M1). The regulatory mechanisms of the IO-NH2-TA 2-TA TNPs@M1 were investigated by evaluating ROS scavenging, degree of hypoxia, adsorption of pro-inflammatory factors, and M2 macrophage polarization. Then, the nano-reactor was incorporated into a dissolving microneedle, utilizing enzyme-cut oligomeric sodium hyaluronate, and subsequently assessed for pharmacodynamics and safety. Results: In vitro mechanisms of IO-NH2-TA 2-TA TNPs@M1 included eliminating ROS, inhibiting the expression of HIF-1 alpha, decreasing the content of pro-inflammatory factors (IL-6 and TNF-alpha), and inducing macrophage M2 polarization. Pharmacodynamic and in vitro mechanistic studies showed that IO-NH2-TA 2-TA TNPs@M1DM maximally alleviated joint swelling and fever, protected joint cartilage, improved the local hypoxia environment and promoted macrophage M2 polarization. Cytotoxicity assays and HE staining showed that IO-NH2-TA 2-TA TNPs@M1DM displayed good biocompatibility. Conclusions: This study designed and synthesized an innovative biomimetic self-enhancing Fenton reaction nano-reactor, and utilized microneedles for the transdermal delivery, providing a scientific and effective new strategy for the precise treatment of RA.

The myocardial ischemia-reperfusion injury (MIRI) is an acute and serious disease with complex pathogenesis, which is intricately associated with oxidative stress, calcium overload, and inflammation. Currently, widely utilized antioxidant or anti-inflammatory strategies present challenges in effectively reversing tissue damage. In this study, a biomimetic targeted mesoporous polydopamine nanoparticle (MR/B@PM) loaded with rapamycin (RAPA) and calcium chelating agent (BAPTA-AM) was successfully constructed, and precise delivery was achieved by a platelet membrane (PM). MR/B@PM facilitated targeted delivery to cardiomyocytes (26-fold) and enhanced intracellular uptake (1.75-fold) compared to MR/B, which was mainly attributed to the natural infarct homing ability of PM and the high affinity between PM and myocardial cells. MR/B@PM significantly inhibited 85.78% of hypoxia-reoxygenation (H/R)-induced cell apoptosis and exerted favorable inhibitory effects on myocardial injury with reduced CK-MB and LDH to 7.61 and 19.43 pg/mL compared to the H/R group. It was proved that MPDA acted as a combined effect with BAPTA-AM and RAPA to inhibit cardiomyocyte apoptosis and modulate the inflammatory response by scavenging ROS and reducing calcium overload. And in the MIRI rat model, MR/B@PM has been demonstrated to significantly reduce serum levels of CK-MB and LDH, while effectively suppressing inflammatory responses. Notably, MR/B@PM effectively reduced infarct size to 19.51% and prevented cardiac remodeling caused by MIRI. This designed nanoplatform comprehensively regulated the multiple pathogenesis of MIRI, which provided an effective strategy and mechanism for the treatment of MIRI.

Ionic liquid transdermal penetration enhancers (IL@TPEs) as new enhancement methods have significant advantages in the transdermal drug delivery system. However, the scientific frameworks for the design of efficient IL@TPEs and their applications in transdermal formulations were still lack. So, a series of novel biomimetic phospholipid-inspired IL@TPEs (PIL@TPEs) were designed and synthesized. The developed QSARs proved that enhancement efficacy of PIL@TPEs depended on pKa of drugs and M.W., Polar., and pKa of cations. Surprisingly, the PIL@TPEs dissociated during transdermal process, and skin penetration amounts of acidic drugs was inversely proportional to skin retention amounts of cations, which showed that action modes of PIL@TPEs were different from conventional enhancers. The novel mechanisms of PIL@TPEs were elucidated by quantitative determination of dynamic interaction among cations, anions, drugs, and skins. The PIL@TPEs with high enhancement efficiency owned strong interactions with drugs determined by ATR-FTIR, Raman and NOESY. Moreover, the PIL@TPEs owning better stability in skin ensured the production of strong interactions with lipids and keratins characterized by ATR-FTIR, 1H NMR and CLSM. The good safety of optimized PIL@TPEs was proved by determining cytotoxicity, apoptosis, inflammatory cells, and cytokines. In conclusion, this project will make an important contribution to the design and application of IL@TPEs.

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs; as novel solvents for improving the solubility of drugs in carriers; as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs; and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

Management of myocardial ischemia-reperfusion injury (MIRI) in reperfusion therapy remains a major obstacle in the field of cardiovascular disease, but current available therapies have not yet been achieved in mitigating myocardial injury due to the complex pathological mechanisms of MIRI. Exogenous delivery of hydrogen sulfide (H2S) to the injured myocardium can be an effective strategy for treating MIRI due to the multiple physiologic functions of H2S, including anti-inflammatory, anti-apoptotic, and mitochondrial protective effects. Here, to realize the precise delivery and release of H2S, we proposed the targeted H2S-mediated gas therapy with pH-sensitive release property mediated by platelet membranes (PMs). In this study, a biomimetic functional poly(lactic-co-ethanolic acid) nanoparticle (RAPA/JK-1-PLGA@PM) was fabricated by loading rapamycin (RAPA; mTOR inhibitor) and JK-1 (H2S donor) and then coated with PM. In vitro observations were conducted including pharmaceutical evaluation, H2S release behaviors, hemolysis analysis, serum stability, cellular uptake, cytotoxicity, inhibition of myocardial apoptosis, and anti-inflammation. In vivo examinations were performed including targeting ability, restoration of cardiac function, inhibition of pathological remodeling, and anti-inflammation. RAPA/JK-1-PLGA@PM was successfully prepared with good size distribution and stability. Utilizing the natural infarct-homing ability of PM, RAPA/JK-1-PLGA@PM could be effectively targeted to the damaged myocardium. RAPA/JK-1-PLGA@PM continuously released H2S triggered by inflammatory microenvironment, which could inhibit cardiomyocyte apoptosis, realize the transition of pro-inflammation, and alleviate myocardial injury demonstrated in hypoxia/reoxygenation myocardial cell in vitro. Precise delivery and release of H2S attenuated inflammatory response and cardiac damage, promoted cardiac repair, and ameliorated cardiac function proven in MIRI mouse model in vivo. This research outlined the novel nanoplatform that combined immunosuppressant agents and H2S donor with the pH-sensitive release property, offering a promising therapeutic for MIRI treatment that leveraged the synergistic effects of gas therapy.

Tumor hypoxia is considered one of the key causes of the ineffectiveness of various strategies for cancer treatment, and the non-specific effects of chemotherapy drugs on tumor treatment often lead to systemic toxicity. Thus, we designed M1 macrophage-biomimetic-targeted nanoparticles (DOX/CAT@PLGA-M1) which contain oxygen self-supplied enzyme (catalase, CAT) and chemo-therapeutic drug (doxorubicin, DOX). The particle size of DOX/CAT@PLGA-M1 was 202.32 ± 2.27 nm (PDI < 0.3). DOX/CAT@PLGA-M1 exhibited a characteristic core-shell bilayer membrane structure. The CAT activity of DOX/CAT@PLGA-M1 was 1000 (U/mL), which indicated that the formation of NPs did not significantly affect its enzymatic activity. And in vitro drug release showed that the cumulative release rate of DOX/CAT@PLGA-M1 was enhanced from 26.93% to 50.10% in the release medium of hydrogen peroxide, which was attributed to the reaction of CAT in the NPs. DOX/CAT@PLGA-M1 displayed a significantly higher uptake in 4T1 cells, because VCAM-1 in tumor cells interacted with specific integrin (α4 and β1), and thereby achieved tumor sites. And the tumor volume of the DOX/CAT@PLGA-M1 group was significantly reduced (0.22 cm3), which further proved the active targeting effect of the M1 macrophage membrane. Above all, a novel multifunctional nano-therapy was developed which improved tumor hypoxia and obtained tumor targeting activity.

Breast cancer has a high prevalence in the world and creates a substantial socio-economic impact. Polymer micelles used as nano-sized polymer therapeutics have shown great advantages in treating breast cancer. Here, we aim to develop a dual-targeted pH-sensitive hybrid polymer (HPPF) micelles for improving the stability, controlled-release ability and targeting ability of the breast cancer treatment options. The HPPF micelles were constructed using the hyaluronic acid modified polyhistidine (HA-PHis) and folic acid modified Plannick (PF127-FA), which were characterized via 1H NMR. The optimized mixing ratio (HA-PHis:PF127-FA) was 8:2 according to the change of particle size and zeta potential. The stability of HPPF micelles were enhanced with the higher zeta potential and lower critical micelle concentration compared with HA-PHis and PF127-FA. The drug release percents significantly increased from 45% to 90% with the decrease in pH, which illustrated that HPPF micelles were pH-sensitive owing to the protonation of PHis. The cytotoxicity, in vitro cellular uptake and in vivo fluorescence imaging experiments showed that HPPF micelles had the highest targeting ability utilizing FA and HA, compared with HA-PHis and PF127-FA. Thus, this study constructs an innovative nano-scaled drug delivery system, which provides a new strategy for the treatment of breast cancer.

Diabetic chronic wounds remain a major clinical challenge with long-term inflammatory responses and extreme oxidative damage. Hence, a pH-responsive injectable multifunctional hydrogel [Gel/CUR-FCHO/Mg (GCM) micromotors] via a Schiff base reaction between gelatin and benzaldehyde-grafted Pluronic F127 drug-loaded micelles (FCHO) was fabricated for the first time. Dynamic Schiff base linkage endowed the GCM hydrogel with the ability to be self-healing, injectable, and pH-responsive for on-demand drug delivery at the wound site. Curcumin (CUR), a hydrophobic drug with antioxidative, anti-inflammatory, and antibacterial activities, was encapsulated into the hydrogel matrix by micellization (CUR-FCHO micelles). Simultaneously, magnesium-based micromotors (Mg micromotors) were physically entrapped into the system for providing active hydrogen (H2) to scavenge reactive oxygen species and alleviate inflammatory responses. As a result, the GCM micromotor hydrogel displayed an inherent antibacterial property, extraordinary antioxidative performance, and remarkable biocompatibility. In the diabetic mouse with a full-thickness cutaneous defect wound, the GCM hydrogel could remodel the inflammatory microenvironment and stimulate vascularization and collagen deposition, thereby facilitating wound closure and enhancing tissue regeneration, which offered a promising therapeutic option for diabetic chronic wound management.

Inflammatory neutrophils (INEs), motivated by cytokines, continue to migrate into the inflamed joints, driving the development of RA. Hence, inducing apoptosis of INEs to reduce recruitment at inflamed joints is an effective strategy for the treatment of RA. However, simply apoptotic INEs may trigger the release of neutrophil extracellular traps (NETs) and accelerate the inflammatory process. To overcome these drawbacks, an RGD-modified bovine serum albumin (BSA) nanoparticles (CBR NPs) was fabricated to selectively target INEs in situ for intracellular delivery of CLT. Studies have demonstrated that CBR NPs can selectively target circulating INEs and induce INEs apoptosis. Meanwhile, CBR NPs inhibited the activation of NETs via NF-κB pathway and the release of Cit-H3 thereby blocking the release process of NETs. In collagen-induced arthritis (CIA) mouse model, CBR NPs suppressed the inflammatory response, and reduced the toxic effects of CLT. In summary, this study shed light on an innovative approach to treat RA by inducing apoptosis of circulating INEs and inhibiting NETs. STATEMENT OF SIGNIFICANCE: RGD-modified bovine serum albumin (BSA) nanoparticles for delivering celastrol, abbreviated as CBR NPs, were constructed to inhibit the infiltration of circulating inflammatory neutrophils (INEs) into inflamed joints while inhibiting the release of NETs to alleviate tissue damage. CBR NPs were prepared for the first time to induce apoptosis of INEs; CBR NPs could inhibit the release of NETs while inducing apoptosis of INEs in vivo and vitro cellular experiments; CBR NPs had favorable anti-inflammatory effects and low toxicity side-effects in collagen-induced arthritis (CIA) mouse models. The application of nanotechnology to induce apoptosis of INEs while inhibiting the release of NETs was a promising approach for the treatment of RA.

作为颅脑疾病的主要表现形式,脑肿瘤、脑梗死等疾病随着全球人口老龄化问题的加剧,发病率逐年增加.其高致残率与致死率促使广大临床与科研工作者开发更安全有效的治疗方法,以应对日渐上升的临床治疗压力.区别于其他部位疾病,脑部疾病治疗中,药物需经外周循环系统由血脑屏障(blood-brain-barrier,BBB)进入脑区发挥效用.BBB阻碍治疗药物在颅内的递送和聚集,限制治疗效果.因此,针对脑部疾病,开发具有特异性、高效性、安全性的治疗体系和递送策略对提高疾病治疗效果至关重要.纳米材料因其组成的多样性和改造的便捷可控性逐渐成为临床问题解决方案储备库,声敏纳米材料因其特殊的超声敏化能力,在颅内疾病的治疗中具有更为明显的优势.本文对具有超声敏化性质的纳米材料在脑肿瘤及脑梗死治疗方面的应用进行总结,并对其未来发展和临床转化进行展望.

Depression is a common mental illness that belongs to the category of emotional disorders that causes serious damage to the health and life of patients, while inflammation is considered to be one of the important factors that causes depression. In this case, it might be important to explore the possible therapeutic approach by using natural compounds exerting an anti-inflammatory and antidepressant effect, which it filed has not been systematically reviewed recently. Hence, this review aims to systematically sort the literature related to the mechanism of exerting an antidepressant effect through anti-inflammatory actions, and to summarize the related natural products in the past 20 years, in terms of a number of inflammatory related pathways (i.e., the protein kinase B (Akt) pathway, monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) (5-HT and NE), the nod-like receptor protein-3 (NLRP3) inflammasome, proinflammatory cytokines, neurotrophins, or cytokine-signaling pathways), which might provide a useful reference for the potential treatment of depression.

A critical obstacle for programmed death ligand 1 (PD-L1) immune checkpoint blockade immunotherapy is the insufficient T cell infiltration and low immunogenicity of tumor cells. Improving tumor immunogenicity through immunogenic cell death (ICD) can make tumor sensitive to PD-L1 checkpoint blockade immunotherapy. Herein, a phenolic based tumor-permeated nano-framework (EGPt-NF) was fabricated by cross-linking phenylboric acid modified platinum nanoparticles (PBA-Pt, ICD inducer) and epigallocatechin-3-O-gallate (EGCG, PD-L1 inhibitor) via pH-reversible borate ester. In particular, PBA-Pt could not only induce ICD cascade but also relieve tumor hypoxia. Consequently, EGPt-NF could effectively promote dendritic cell maturation and downregulate PD-L1 expression in tumor cells. Furthermore, EGPt-NF could also relieve tumor hypoxia to facilitate cytotoxic T lymphocyte infiltration and IFN-γ secretion. The synergistic effect of EGPt-NF could effectively improve tumor immunogenicity and amplify the therapeutic outcomes of cancer immunotherapy, resulting in a strong antitumor immune response in primary tumor and metastasis inhibition. Our simple approach expands the application of platinum-based drug delivery systems for cancer immunotherapy.

Cerebral ischemic injury is an important factor affecting the prognosis of acute ischemic stroke (AIS). Neuronal apoptosis and the change in microglial phenotype have been implicated in the development of AIS. The changes in microglia from the M1 phenotype to the M2 phenotype could rescue neurons and reduce apoptosis. MiRNA-Let-7c reduced ischemic injury by regulating the survival of neurons and changing microglial phenotype. Here, we used the information regarding the changes in the brain microenvironment after ischemic injury and constructed pH-sensitive polymeric nanoparticles to deliver miRNA-Let-7c. The nanoparticles were coated with platelet membrane, which preserved the function of platelets while allowing nanoparticles to evade recognition by the immune system. The platelet membrane-camouflaged nanoparticles entered the neutrophils by endocytosis and used inflammatory chemotaxis of neutrophils to transport the vector across the blood-brain barrier (BBB). The platelet membrane-camouflaged nanoparticles efficiently localized to the area of the ischemic injury and delivered the miRNA-Let-7c for the targeted regulation of neurons and microglia. Based on these results, we conclude that this strategy is a favorable gene delivery system and could effectively treat ischemic injury. (C) 2022 Elsevier Ltd. All rights reserved.

Increase extracellular adenosine triphosphate (ATP, a necessary eat me signal for ICD) is a facile way to amplify immunogenic cell death (ICD) cascade for cancer immunotherapy. However, it is still challenging for intra-tumoral delivery ATP due to complicated enzyme environment in the whole body. Furthermore, tumor immu-nosuppressive microenvironment (TIM) also hampers the function of mature DCs and limit the activation of immune response. To overcome these drawbacks, a tumor-permeated ATP-based immunogenic cell death amplifier (NABP@SNCs) is fabricated for the first time. (Phenylboronic acid-polyethylene glycol-phenylboronic acid) PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles (ABP) is constructed and interacted with ATP through borate ester bond. Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 and ABP are co-wrapped with MMP-2 sensitive framework to form NABP@SNCs. NABP@SNCs can not only protect ATP degradation but also release small sized ABP under MMP-2 microenvironment for tumor penetration. Interestingly, ATP can also be released into extracellular regions in tumor acidic pH and act as 'eat me signal' for DCs maturation. Synergistically ICD activation by BP (PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles) and TIM reversal by NLG919 can facilitate T lymphocyte cells infiltration for immune response. NABP@SNCs can significantly regress tumor growth and reduce pulmonary metastasis for improved cancer immunotherapy.

Amplifying "eat me signal" during tumor immunogenic cell death (ICD) cascade is crucial for tumor immunotherapy. Inspired by the indispensable role of adenosine triphosphate (ATP, a necessary "eat me signal" for ICD), a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy. Doxorubicin (DOX), ATP and ferrous ions (Fe2+) were co-assembled into nanosized amplifier (ADO-Fe) through π‒π stacking and coordination effect. Meanwhile, phenylboric acid-polyethylene glycol-phenylboric acid (PBA-PEG-PBA) was modified on the surface of ADO-Fe (denoted as PADO-Fe) by the virtue of d-ribose unit of ATP. PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction. In acidic microenvironment, PBA-PEG-PBA would dissociate from amplifier. Moreover, high H2O2 concentration would induce hydroxyl radical (·OH) and oxygen (O2) generation through Fenton reaction by Fe2+. DOX and ATP would be released from the amplifier, which could induce ICD effect and "ICD adjuvant" to amplify this process. Together with programmed death ligands 1 (PD-L1) checkpoint blockade immunotherapy, PADO-Fe could not only activate immune response against primary tumor, but also strong abscopal effect against distant tumor. Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.

The tumor immunosuppressive microenvironment (TIM) greatly hindered the efficacy of cancer immunotherapy. Overexpressed indoleamine 2,3-dioxygenase-1 (IDO1) in tumor tissues plays a vital role in TIM generation, and downregulation of IDO1 expression may reverse TIM. Inspired by the Watson-Crick base-pairing rule, a versatile noncationic miRNA vector (miDAC@PDA) is developed for cancer immunotherapy. Doxorubicin (DOX), adenosine triphosphate (ATP), and copper ions (Cu2+) are coassembled into coordination polymer nanoparticles (DAC) and bind miRNA via the hydrogen bond interaction (miDAC) between adenine residues (ATP) and uracil residues (miRNA). Polydopamine (PDA) is deposited onto the surface of miDAC for photothermal therapy. miDAC@PDA can efficiently accumulate into tumor tissues for cellular uptake. Under laser irradiation and high intracellular GSH levels, the PDA shell of miDAC@PDA can dissociate from miDAC for miRNA release due to local hyperthermia. Cu2+-mediated GSH consumption and intracellular ATP release can amplify the DOX-based immunogenic cell death (ICD) cascade, together with miR-448-mediated IDO1 inhibition, and these versatile nanoplexes will not only restrain primary tumor growth but also display a remarkable abscopal effect on distant tumors. Collectively, our study provides a unique strategy for intracellular gene delivery and an inspirational approach for multimechanism cancer management.