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Active matter therapeutics. Nano today Nanotherapies based on micelles, liposomes, polymersomes, nanocapsules, magnetic nanoparticles, and noble metal nanoparticles have been at the forefront of drug delivery in the past few decades. Some of these nanopharmaceuticals have been commercially applied to treat a wide range of diseases, from dry eye syndrome to cancer. However, the majority involve particles that are passive, meaning that they do not change shape, and they lack motility; the static features can limit their therapeutic efficacy. In this review, we take a critical look at an emerging field that seeks to utilize active matter for therapeutics. In this context, active matter can be broadly referred to as micro or nanosized constructs that energetically react with their environment or external fields and translate, rotate, vibrate or change shape. Essentially, the recent literature suggests that such particles could significantly augment present-day drug delivery, by enhancing transport and increasing permeability across anatomical barriers by transporting drugs within solid tumor microenvironments or disrupting cardiovascular plaque. We discuss examples of such particles and link the transport and permeability properties of active matter to potential therapeutic applications in the context of two major diseases, namely cancer and heart disease. We also discuss potential challenges, opportunities, and translational hurdles. 10.1016/j.nantod.2019.100836
Pyroelectric Catalysis-Based "Nano-Lymphatic" Reduces Tumor Interstitial Pressure for Enhanced Penetration and Hydrodynamic Therapy. He Yuchu,Li Zhuo,Cong Cong,Ye Fei,Yang Jingyue,Zhang Xuwu,Yuan Yi,Ma Zhenhe,Zhang Kaiqing,Lin Yang,Zheng Lizhao,Liang Xing-Jie,Gao Dawei ACS nano Because of the deficiency of lymphatic reflux in the tumor, the retention of tumor interstitial fluid causes aggravation of the tumor interstitial pressure (TIP), which leads to unsatisfactory tumor penetration of nanomedicine. It is the main inducement of tumor recurrence and metastasis. Herein, we design a pyroelectric catalysis-based "Nano-lymphatic" to decrease the TIP for enhanced tumor penetration and treatments. It realizes photothermal therapy and decomposition of tumor interstitial fluid under NIR-II laser irradiation after reaching the tumor, which reduces the TIP for enhanced tumor penetration. Simultaneously, reactive oxygen species generated during the pyroelectric catalysis can further damage deep tumor stem cells. The results indicate that the "Nano-lymphatic" relieves 52% of TIP, leading to enhanced tumor penetration, which effectively inhibits the tumor proliferation (93.75%) and recurrence. Our finding presents a rational strategy to reduce TIP by pyroelectric catalysis for enhanced tumor penetration and improved treatments, which is of great significance for drug delivery. 10.1021/acsnano.1c03048
Facet-Dependent Biodegradable Mn O Nanoparticles for Ameliorating Parkinson's Disease. Xu Zhuojia,Qu Aihua,Wang Weiwei,Lu Meiru,Shi Baimei,Chen Chen,Hao Changlong,Xu Liguang,Sun Maozhong,Xu Chuanlai,Kuang Hua Advanced healthcare materials Parkinson's disease (PD) is a common neurodegeneration disease. Unfortunately, there are no effective measures to prevent or inhibit this disease. In this study, biodegradable Mn O nanoparticles (NPs) in different shapes are prepared and enclosed them by {100}, {200} and {103} facets that exhibit facet-dependent protection against neurotoxicity induced by oxidative damage in a cell model of PD. Notably, Mn O nanorods enclosed by {103} facets exhibit high levels of enzyme-like activity to eliminate reactive oxygen specie in vitro. It is also determined that the uptake pathway of Mn O NPs into MN9D cells is mediated by caveolin. The data demonstrate that Mn O nanorods can be taken up by cells effectively and confer excellent levels of neuroprotection while the biodegradation of Mn O NPs in vivo is confirmed by photoacoustic image of Mn O NPs in brain at 60 d. Furthermore, the oxygen scavenging effect created by Mn O nanorods is successfully applied to a mouse model of PD; the amount of α-synuclein in the cerebrospinal fluid of PD mice is reduced by 61.2% in two weeks, thus demonstrating the potential application of facet-directed Mn O NPs for the clinical therapy of neurodegenerative disease. 10.1002/adhm.202101316
Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis. Nature aging Alzheimer's disease (AD) is characterized by amyloid-β accumulation in the brain and hyperphosphorylated tau aggregation, as well as neuroinflammation. The gut-brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling. Here we investigate interactions between orally ingested chiral Au nanoparticles and the gut microbiota in AD mice. Oral administration of chiral Au nanoparticles restored cognitive abilities and ameliorated amyloid-β and hyperphosphorylated tau pathologies in AD mice via alterations in the gut microbiome composition and an increase in the gut metabolite, indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls. Oral administration of indole-3-acetic acid was able to penetrate the blood-brain barrier and alleviated cognitive decline and pathology including neuroinflammation in AD mice. These findings provide a promising therapeutic target for the amelioration of neuroinflammation and treatment of neurodegenerative diseases. 10.1038/s43587-023-00516-9
Selenium Nanoparticles as an Efficient Nanomedicine for the Therapy of Huntington's Disease. Cong Wenshu,Bai Ru,Li Yu-Feng,Wang Liming,Chen Chunying ACS applied materials & interfaces Huntington's disease (HD) is an incurable disease with progressive loss of neural function, which is influenced by epigenetic, oxidative stress, metabolic, and nutritional factors. Targeting inhibition of huntingtin protein aggregation is a strategy for HD therapy, but the efficacy is unsatisfactory. Studies found that selenium (Se) levels in the brain are insufficient for HD disease individuals, while improvement in Se homeostasis in the brain may attenuate neuronal loss and dysfunction. In this study, we applied selenium nanoparticles (NPs) (Nano-Se) for the HD disease therapy by regulating HD-related neurodegeneration and cognitive decline based on transgenic HD models of (). At low dosages, Nano-Se NPs significantly reduced neuronal death, relieved behavioral dysfunction, and protected from damages in stress conditions. The molecular mechanism further revealed that Nano-Se attenuated oxidative stress, inhibited the aggregation of huntingtin proteins, and downregulated the expression of histone deacetylase family members at mRNA levels. The results suggested that Nano-Se has great potential for Huntington's disease therapy. In conclusion, the mechanism about how Nano-Se NPs protect from damages in stress conditions and how they repair neural functions will benefit HD disease therapy. This study will also guide rational design of Nano-Se NPs or other selenium compounds to improve HD therapy in the future. 10.1021/acsami.9b12319
Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model. Adhikari Aniruddha,Mondal Susmita,Das Monojit,Biswas Pritam,Pal Uttam,Darbar Soumendra,Bhattacharya Siddhartha Sankar,Pal Debasish,Saha-Dasgupta Tanusri,Das Anjan Kumar,Mallick Asim Kumar,Pal Samir Kumar Advanced healthcare materials The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, it is shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn O NP) efficiently mimics glutathione peroxidase (GPx) enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H O scavenging. A detailed computational study reveals the mechanism of the nanozyme action. The in vivo therapeutic efficacy of C-Mn O nanozyme is further established in a preclinical animal model of Huntington's disease (HD), a prevalent progressive neurodegenerative disorder, which has no effective medication to date. Management of HD in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy. 10.1002/adhm.202001736
Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier. Advanced materials (Deerfield Beach, Fla.) Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases. 10.1002/adma.202405323
Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms. Nature nanotechnology Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders. 10.1038/s41565-024-01683-5
Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability. Journal of controlled release : official journal of the Controlled Release Society The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced HO-induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only. 10.1016/j.jconrel.2023.06.001
Engineered Extracellular Vesicle-Based Nanoformulations That Coordinate Neuroinflammation and Immune Homeostasis, Enhancing Parkinson's Disease Therapy. ACS nano Although conventional intervention to microglia can mitigate neuroinflammation in the short term, immune disorders by peripheral inflammatory cells can infiltrate continuously, resulting in an overactivated immune microenvironment of Parkinson's disease (PD). Here, we design engineered extracellular vesicle-based nanoformulations (EVNs) to address multiple factors for the management of PD. Specifically, EVN is developed by coating CCR2-enriched mesenchymal stem cell-derived extracellular vesicles (MSC EVs) onto a dihydrotanshinone I-loaded nanocarrier (MSeN-DT). The MSC EVs (the shell of EVN) can actively show homing to specific chemokines CCL2 in the substantia nigra, which enables them to block the infiltration of peripheral inflammatory cells. Interestingly, MSeN-DT (the core of EVN) can promote the Nrf2-GPX4 pathway for the suppression of the source of inflammation by inhibiting ferroptosis in microglia. In the PD model mice, a satisfactory therapeutic effect is achieved, with inhibition of peripheral inflammatory cell infiltration, precise regulation of inflammatory microglia in the substantia nigra, as well as promotion of behavioral improvement and repairing damaged neurons. In this way, the combinatorial code of alleviation of inflammation and modulation of immune homeostasis can reshape the immune microenvironment in PD, which bridges internal anti-inflammatory and external immunity. This finding reveals a comprehensive therapeutic paradigm for PD that breaks the vicious cycle of immune overactivation. 10.1021/acsnano.4c04674
Nanoarmour-shielded single-cell factory for bacteriotherapy of Parkinson's disease. Zhou Xin,Guo Qinglu,Guo Mingming,Li Bowen,Peng Wenchang,Wang Deping,Ming Dong,Zheng Bin Journal of controlled release : official journal of the Controlled Release Society Cell-based therapy for Parkinson's disease (PD) is a novel and promising approach in recent years. However, exogenous cells are easy to be captured and destroyed by the harsh environment in vivo, so their application prospects have been severely limited. Here, a facile yet versatile approach for decorating individual living cells with nano-armor coatings is reported. By simply self-assembly with liposome under a cyto-compatible condition, the lipid bimolecular coating on the surface of each cell acts as armor to effectively protect it from the attack and destruction of strong acids and digestive enzymes during the oral treatment of PD. Our results demonstrated that the liposome coated B. adolescentis (LCB) could significantly improve the colonization rate in the intestinal tract. LCB, as a living cell factory, can self-regulate to produce a constant concentration of γ-aminobutyric acid and maintain a longer half-life for the treatment of PD. Then, we also explored the specific mechanism of LCB to improve the behavior of murine models of PD, including abating inflammatory effects, reducing neuronal apoptosis, regulating the activity of dopaminergic neurons and microglia. The simple nano-armor shielded single-cell factory can produce neurotransmitters-like drugs on demand in vivo, introducing novel strategies of integration of producing and using to the research of drug delivery field. 10.1016/j.jconrel.2021.09.009
Facilitating Pro-survival Mitophagy for Alleviating Parkinson's Disease via Sequence-Targeted Lycopene Nanodots. ACS nano The pathogenesis of Parkinson's disease is closely linked to impaired mitochondrial function and abnormal mitophagy. Biocompatible natural antioxidants effectively protect dopaminergic neurons. However, the main challenge in using natural antioxidants for Parkinson's disease therapy is creating a delivery platform to achieve neuron-targeted enrichment. Herein, we synthesized rationally sequence-targeted lycopene nanodots using recombinant human H-ferritin nanocages with lycopene loading into the cavity and lipophilic triphenylphosphonium (TPP) coupling on the outer surface. The nanodots allow for the neural enrichment and mitochondrial regulation of lycopene through blood-brain barrier transcytosis and neuronal mitochondria-targeting capability. These anti-ROS nanodots protect neuronal mitochondrial function and promote PINK1/Parkin-mediated mitophagy in MPTP toxicity-induced neurons and , which favors the secretory efflux of pathogenic α-synuclein and the survival of dopaminergic neurons. Moreover, these nanodots restore the Parkinson-like motor symptoms in Parkinson's model mice. This noninvasive sequence-targeted delivery strategy with excellent biocompatibility for pro-survival mitophagy-mediated pathology alleviation makes it a promising approach for treating and preventing Parkinson's disease. 10.1021/acsnano.3c04308
Repositioning of drugs for Parkinson's disease and pharmaceutical nanotechnology tools for their optimization. Journal of nanobiotechnology Parkinson's disease (PD) significantly affects patients' quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors "Parkinson's disease" and "drug repositioning" or "drug repurposing". We identified 28 drugs as potential candidates, and six of them were found in repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their inability to cross the blood-brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential. Finally, current advances in the use of NPs for Parkinson's disease are cited. 10.1186/s12951-022-01612-5
A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease. Liu Jingyi,Liu Chao,Zhang Jinfeng,Zhang Yunming,Liu Keyin,Song Ju-Xian,Sreenivasmurthy Sravan Gopalkrishnashetty,Wang Ziying,Shi Yesi,Chu Chengchao,Zhang Yang,Wu Caisheng,Deng Xianhua,Liu Xingyang,Song Jing,Zhuang Rongqiang,Huang Shuqiong,Zhang Pengfei,Li Min,Wen Lei,Zhang Yun Wu,Liu Gang ACS nano Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD. 10.1021/acsnano.9b06453
Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson's disease treatment via cooperative modulation of microglia. Bioactive materials Effective treatment of Parkinson's disease (PD), a prevalent central neurodegenerative disorder particularly affecting the elderly population, still remains a huge challenge. We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers (termed as AK123) complexed with fibronectin (FN) with anti-inflammatory and antioxidative activities. The created optimized AK123/FN nanocomplexes (NCs) with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting. We show that the AK123/FN NCs are able to consume excessive reactive oxygen species, promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors. With the abundant dendrimer surface hydroxyl terminal groups, the developed NCs are able to cross blood-brain barrier (BBB) to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects, thus reducing the aggregation of α-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels . The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive phosphorus dendrimers and FN, which is expected to be extended for the treatment of different neurodegenerative diseases. 10.1016/j.bioactmat.2024.04.005
Nano-MgO composites containing plasmid DNA to silence SNCA gene displays neuroprotective effects in Parkinson's rats induced by 6-hydroxydopamine. European journal of pharmacology Parkinson's disease (PD) always causes dyskinesia and cognitive impairments. The alpha-synuclein (α-syn) accumulation, one of the main pathological characteristics of PD, may impair synaptic structural and synaptic functions. Nano-MgO composites has been reported to interfere α-syn expression. The present study is aim to investigate the roles of nano-MgO composites on cognitive impairments in PD rats. PD rats were formed by 6-hydroxydopamine (6-OH DA) and α-syn expression were evaluated by Western blot. Hippocampal dendritic morphology was examined by Golgi staining. Morris water maze (MWM) test was applied to evaluate learning and memory abilities and population spike was recorded by electrophysiological records in vivo. The results showed that: 6-OH DA-treated up-regulated α-syn levels in striatum and hippocampus and increased the rotational times by APO, but nano-MgO composites could down-regulated α-syn levels. The overall length of dendritic and the total number of intersections were reduced by 6-OH DA, accompanied by the decrease of the dendritic spine density in hippocampal CA1, CA3 and DG regions. Interestingly, nano-MgO composites could alleviate the morphological damages of dendrites. In the MWM test, the escape latencies and the swimming distances in PD rats were increased as compared to the sham group, and nano-MgO composites could reduce the escapes latencies and the swimming distances. Furthermore, 6-OH DA reduced the amplitudes of long-term potentiation (LTP) in hippocampal CA1 region, and 6 mg/kg nano-MgO composites could improve LTP amplitudes. In conclusion, the current findings would be helpful to explore the roles of nano-MgO composites on neuroprotection in PD. 10.1016/j.ejphar.2022.174904
Chemoimmunotherapeutic Nanogel for Pre- and Postsurgical Treatment of Malignant Melanoma by Reprogramming Tumor-Associated Macrophages. Nano letters Surgery is the primary method to treat malignant melanoma; however, the residual microtumors that cannot be resected completely often trigger tumor recurrence, causing tumor-related mortality following melanoma resection. Herein, we developed a feasible strategy based on the combinational chemoimmunotherapy by cross-linking carboxymethyl chitosan (CMCS)-originated polymetformin (PolyMet) with cystamine to prepare stimuli-responsive nanogel (PMNG) owing to the disulfide bond in cystamine that can be cleaved by the massive glutathione (GSH) in tumor sites. Then, chemotherapeutic agent doxorubicin (DOX) was loaded in PMNG, which was followed by a hyaluronic acid coating to improve the overall biocompatibility and targeting ability of the prepared nanogel (D@HPMNG). Notably, PMNG effectively reshaped the tumor immune microenvironment by reprogramming tumor-associated macrophage phenotypes and recruiting intratumoral CD8 T cells owing to the inherited immunomodulatory capability of metformin. Consequently, D@HPMNG treatment remarkably suppressed melanoma growth and inhibited its recurrence after surgical resection, proposing a promising solution for overcoming lethal melanoma recurrence. 10.1021/acs.nanolett.3c04563
Co-delivery Nano System of MS-275 and V-9302 Induces Pyroptosis and Enhances Anti-Tumor Immunity Against Uveal Melanoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self-rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)-responsive nanoparticles (NPs) are designed that encapsulate HDACi MS-275 and the glutamine metabolism inhibitor V-9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS-275 to increase the level of ROS and V-9302 to reduce the production of glutathione (GSH) related to self-rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α-PD-1), these NPs facilitate immune cell infiltration, improving anti-tumor immunity, converting "immune-cold" tumors into "immune-hot" tumors, and enhancing immune memory in mice. The findings present a nano-delivery strategy for the co-delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy. 10.1002/advs.202404375
A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy. ACS nano Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSC that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy. 10.1021/acsnano.4c03172
Nanoparticles mediated tumor microenvironment modulation: current advances and applications. Journal of nanobiotechnology The tumor microenvironment (TME) plays a key role in cancer development and emergence of drug resistance. TME modulation has recently garnered attention as a potential approach for reprogramming the TME and resensitizing resistant neoplastic niches to existing cancer therapies such as immunotherapy or chemotherapy. Nano-based solutions have important advantages over traditional platform and can be specifically targeted and delivered to desired sites. This review explores novel nano-based approaches aimed at targeting and reprogramming aberrant TME components such as macrophages, fibroblasts, tumor vasculature, hypoxia and ROS pathways. We also discuss how nanoplatforms can be combined with existing anti-tumor regimens such as radiotherapy, immunotherapy, phototherapy or chemotherapy to enhance clinical outcomes in solid tumors. 10.1186/s12951-022-01476-9