Bee chitosan nanoparticles loaded with apitoxin as a novel approach to eradication of common human bacterial, fungal pathogens and treating cancer.

Antimicrobial resistance is one of the largest medical challenges because of the rising frequency of opportunistic human microbial infections across the globe. This study aimed to extract chitosan from the exoskeletons of dead bees and load it with bee venom (commercially available as Apitoxin [Api]). Then, the ionotropic gelation method would be used to form nanoparticles that could be a novel drug-delivery system that might eradicate eight common human pathogens (i.e., two fungal and six bacteria strains). It might also be used to treat the human colon cancer cell line (Caco2 ATCC ATP-37) and human liver cancer cell line (HepG2ATCC HB-8065) cancer cell lines. The x-ray diffraction (XRD), Fourier transform infrared (FTIR), and dynamic light scattering (DLS) properties, ζ-potentials, and surface appearances of the nanoparticles were evaluated by transmission electron microscopy (TEM). FTIR and XRD validated that the Api was successfully encapsulated in the chitosan nanoparticles (ChB NPs). According to the TEM, the ChB NPs and the ChB NPs loaded with Apitoxin (Api@ChB NPs) had a spherical shape and uniform size distribution, with non-aggregation, for an average size of approximately 182 and 274 ± 3.8 nm, respectively, and their Zeta potential values were 37.8 ± 1.2 mV and - 10.9 mV, respectively. The Api@ChB NPs had the greatest inhibitory effect against all tested strains compared with the ChB NPs and Api alone. The minimum inhibitory concentrations (MICs) of the Api, ChB NPs, and Api@ChB NPs were evaluated against the offer mentioned colony forming units (CFU/mL), and their lowest MIC values were 30, 25, and 12.5 µg mL-1, respectively, against Enterococcus faecalis. Identifiable morphological features of apoptosis were observed by 3 T3 Phototox software after Api@ChB NPs had been used to treat the normal Vero ATCC CCL-81, Caco2 ATCC ATP-37, and HepG2 ATCC HB-8065 cancer cell lines for 24 h. The morphological changes were clear in a concentration-dependent manner, and the ability of the cells was 250 to 500 µg mL-1. These results revealed that Api@ChB NPs may be a promising natural nanotreatment for common human pathogens.

Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management.

The advent of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of malignant solid tumors in the last decade, producing lasting benefits in a subset of patients. However, unattended excessive immune responses may lead to immune-related adverse events (irAEs). IrAEs can manifest in different organs within the body, with pulmonary toxicity commonly referred to as immune checkpoint inhibitor-related pneumonitis (CIP). The CIP incidence remains high and is anticipated to rise further as the therapeutic indications for ICIs expand to encompass a wider range of malignancies. The diagnosis and treatment of CIP is difficult due to the large individual differences in its pathogenesis and severity, and severe CIP often leads to a poor prognosis for patients. This review summarizes the current state of clinical research on the incidence, risk factors, predictive biomarkers, diagnosis, and treatment for CIP, and we address future directions for the prevention and accurate prediction of CIP.

Gut microbiota and dietary intervention: affecting immunotherapy efficacy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. In recent years, treatment with immune checkpoint inhibitors (ICIs) has gradually improved the survival rate of patients with NSCLC, especially those in the advanced stages. ICIs can block the tolerance pathways that are overexpressed by tumor cells and maintain the protective activity of immune system components against cancer cells. Emerging clinical evidence suggests that gut microbiota may modulate responses to ICIs treatment, possibly holding a key role in tumor immune surveillance and the efficacy of ICIs. Studies have also shown that diet can influence the abundance of gut microbiota in humans, therefore, dietary interventions and the adjustment of the gut microbiota is a novel and promising treatment strategy for adjunctive cancer therapy. This review comprehensively summarizes the effects of gut microbiota, antibiotics (ATBs), and dietary intervention on the efficacy of immunotherapy in NSCLC, with the aim of informing the development of novel strategies in NSCLC immunotherapy.

The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside.

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance.

Extracellular vesicles (EVs) act as multifunctional regulators of intercellular communication and are involved in diverse tumor phenotypes, including tumor angiogenesis, which is a highly regulated multi-step process for the formation of new blood vessels that contribute to tumor proliferation. EVs induce malignant transformation of distinct cells by transferring DNAs, proteins, lipids, and RNAs, including noncoding RNAs (ncRNAs). However, the functional relevance of EV-derived ncRNAs in tumor angiogenesis remains to be elucidated. In this review, we summarized current research progress on the biological functions and underlying mechanisms of EV-derived ncRNAs in tumor angiogenesis in various cancers. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as cancer biomarkers and novel therapeutic targets to tailor anti-angiogenic therapy.

The potential role of exosomal circRNAs in the tumor microenvironment: insights into cancer diagnosis and therapy.

Exosomes are multifunctional regulators of intercellular communication by carrying various messages under both physiological and pathological status of cancer patients. Accumulating studies have identified the presence of circular RNAs (circRNAs) in exosomes with crucial regulatory roles in diverse pathophysiological processes. Exosomal circRNAs derived from donor cells can modulate crosstalk with recipient cells locally or remotely to enhance cancer development and propagation, and play crucial roles in the tumor microenvironment (TME), leading to significant enhancement of tumor immunity, metabolism, angiogenesis, drug resistance, epithelial mesenchymal transition (EMT), invasion and metastasis. In this review, we describe the advances of exosomal circRNAs and their roles in modulating cancer hallmarks, especially those in the TME. Moreover, clinical application potential of exosomal circRNAs in cancer diagnosis and therapy are highlighted, bridging the gap between basic knowledge and clinical practice.

Long non-coding RNAs and circular RNAs in tumor angiogenesis: From mechanisms to clinical significance.

Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) execute a wide array of functions in physiological and pathological processes, including tumor progression. Angiogenesis, an elaborate multistep process driving new blood vessel formation, accelerates cancer progression by supplying nutrients and energy. Dysregulated lncRNAs and circRNAs can reportedly impact cancer progression by influencing angiogenesis. However, the expanding landscape of lncRNAs and circRNAs in tumor progression-dependent angiogenesis remains largely unknown. This review summarizes the major functions of angiogenic lncRNAs (Angio-LncRs) and angiogenic circRNAs (termed Angio-CircRs) and their cancer mechanisms. Moreover, we highlight the commonalities of lncRNAs and circRNAs in epigenetic, transcriptional, and post-transcriptional regulation as well as illustrate how Angio-LncRs and Angio-CircRs induce cancer onset and progression. We also discuss their potential clinical applications in diagnosis, prognosis, and anti-angiogenic therapies.

Upgrading of Light Bio-oil from Solvothermolysis Liquefaction of an Oil Palm Empty Fruit Bunch in Glycerol by Catalytic Hydrodeoxygenation Using NiMo/Al2O3 or CoMo/Al2O3 Catalysts.

Hydrodeoxygenation (HDO) of bio-oil derived from liquefaction of a palm empty fruit bunch (EFB) in glycerol was investigated. To enhance the heating value and reduce the oxygen content of upgraded bio-oil, hydrodeoxygenation of light bio-oil over Ni- and Co-based catalysts on an Al2O3 support was performed in a rotating-bed reactor. Two consecutive steps were conducted to produce bio-oil from EFB including (1) microwave-assisted wet torrefaction of EFB and (2) solvothermolysis liquefaction of treated EFB in a Na2CO3/glycerol system. The HDO of as-prepared bio-oil was subsequently performed in a unique design reactor possessing a rotating catalyst bed for efficient interaction of a catalyst with bio-oil and facile separation of the catalyst from upgraded bio-oil after the reaction. The reaction was carried out in the presence of each mono- or bimetallic catalyst, namely, Co/Al2O3, Ni/Al2O3, NiMo/Al2O3, and CoMo/Al2O3, packed in the rotating-mesh host with a rotation speed of 250 rpm and kept at 300 and 350 °C, 2 MPa hydrogen for 1 h. From the results, the qualities of upgraded bio-oil were substantially improved for all catalysts tested in terms of oxygen reduction and increased high heating value (HHV). Particularly, the NiMo/Al2O3 catalyst exhibited the most promising catalyst, providing favorable bio-oil yield and HHV. Remarkably greater energy ratios and carbon recovery together with high H/O, C/O, and H/C ratios were additionally achieved from the NiMo/Al2O3 catalyst compared with other catalysts. Cyclopentanone and cyclopentene were the main olefins found in hydrodeoxygenated bio-oil derived from liquefied EFB. It was observed that cyclopentene was first generated and subsequently converted to cyclopentanone under the hydrogenation reaction. These compounds can be further used as a building block in the synthesis of jet-fuel range cycloalkanes.

Gut microbiota homeostasis restoration may become a novel therapy for breast cancer.

Breast cancer is the most diagnosed cancer in women. It significantly impairs a patient's physical and mental health. Gut microbiota comprise the bacteria residing in a host's gastrointestinal tract. Through studies over the last decade, we now know that alterations in the composition of the gut microbiome are associated with protection against colonization by pathogens and other diseases, such as diabetes and cancer. This review focuses on how gut microbiota can affect breast cancer development through estrogen activity and discusses the types of bacteria that may be involved in the onset and the progression of breast cancer. We also describe potential therapies to curtail the risk of breast cancer by restoring gut microbiota homeostasis and reducing systemic estrogen levels. This review will further explore the relationship between intestinal microbes and breast cancer and propose a method to treat breast cancer by improving intestinal microbes. We aimed at discovering new methods to prevent or treat BC by changing intestinal microorganisms.

Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?

Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.

Macrophages-targeting mannosylated nanoparticles based on inulin for the treatment of inflammatory bowel disease (IBD).

In the present experimental series, we have developed a novel nanocomposite to target activated macrophages in the colon with real time imaging and therapeutic capabilities. This binary nanocomposite was formed by the covalent conjugation of mannosylated NPs (Man-NPs) with carbon dots (CDs). Man-NPs were prepared using a self-assembly method based on mannosylated decamethylenediamine-grafted carboxymethyl inulin amphiphilic acid. While, the CDs were synthesized using a simple bottom-up process using citric acid monohydrate and diethylenetriamine, which were tightly bonded to the Man-NPs surface by carbodimide coupling. The resulting nanocomposite had a uniform size of 241.3 nm with a negative charge and a high drug casing density of 25.54 wt% and blue self-fluorescence were emitted. Whereas, in vitro observation of cellular uptake indicated the greater nanocomposite uptake in inflamed macrophage as compared to the untreated macrophage and mannose receptor-negative cell lines, 4T1 respectively. However, in vivo bio distribution exhibited a large number (60%) of CDs/Man-NPs nanocomposite accumulated in the inflamed colon of colitis mice. It should be noted that the novel nanocomposite, as macrophage-targeted drug delivery, could have promise for the treatment of inflammatory bowel disease (IBD).

Biodegradable Quantum Composites for Synergistic Photothermal Therapy and Copper-Enhanced Chemotherapy.

In recent times, the combination therapy has garnered enormous interest owing to its great potential in clinical research. It has been reported that disulfiram, a clinical antialcoholism drug, could be degraded to diethyldithiocarbamate (DDTC) in vivo and subsequently result in the copper-DDTC complex (Cu(DDTC)2) toward ablating cancer cells. In addition, the ultrasmall copper sulfide nanodots (CuS NDs) have shown great potential in cancer treatment because of their excellent photothermal and photodynamic therapeutic efficiencies. Herein, by taking advantage of the interactions between CuS and DDTC, a new multifunctional nanoplatform based on DDTC-loaded CuS (CuS-DDTC) NDs is successfully fabricated, leading to the achievement of the synergistic effect of photothermal and copper enhanced chemotherapy. All experimental results verified promising synergistic therapeutic effects. Moreover, in vivo biocompatibility and metabolism experiments displayed that the CuS-DDTC NDs could be quickly excreted from the body with no apparent toxicity signs. Together, our findings indicated the superior synergistic therapeutic effect of photothermal and copper-enhanced chemotherapy, providing a promising anticancer strategy based on the CuS-DDTC NDs drug delivery system.

Near-Infrared-Activated Lysosome Pathway Death Induced by ROS Generated from Layered Double Hydroxide-Copper Sulfide Nanocomposites.

The overdeveloped lysosomes in cancer cells are gaining increasing attention toward more precise and effective organelle-targeted cancer therapy. It is suggested that rod/plate-like nanomaterials with an appropriate size exhibited a greater quantity and longer-term lysosomal enrichment, as the shape plays a notable role in the nanomaterial transmembrane process and subcellular behaviors. Herein, a biodegradable platform based on layered double hydroxide-copper sulfide nanocomposites (LDH-CuS NCs) is successfully prepared via in situ growth of CuS nanodots on LDH nanoplates. The as-prepared LDH-CuS NCs exhibited not only high photothermal conversion and near-infrared (NIR)-induced chemodynamic and photodynamic therapeutic efficacies, but also could achieve real-time in vivo photoacoustic imaging (PAI) of the entire tumor. LDH-CuS NCs accumulated in lysosomes would then generate extensive subcellular reactive oxygen species (ROS) in situ, leading to lysosomal membrane permeabilization (LMP) pathway-associated cell death both in vitro and in vivo.

Subcellular Performance of Nanoparticles in Cancer Therapy.

With the advent of nanotechnology, various modes of traditional treatment strategies have been transformed extensively owing to the advantageous morphological, physiochemical, and functional attributes of nano-sized materials, which are of particular interest in diverse biomedical applications, such as diagnostics, sensing, imaging, and drug delivery. Despite their success in delivering therapeutic agents, several traditional nanocarriers often end up with deprived selectivity and undesired therapeutic outcome, which significantly limit their clinical applicability. Further advancements in terms of improved selectivity to exhibit desired therapeutic outcome toward ablating cancer cells have been predominantly made focusing on the precise entry of nanoparticles into tumor cells via targeting ligands, and subsequent delivery of therapeutic cargo in response to specific biological or external stimuli. However, there is enough room intracellularly, where diverse small-sized nanomaterials can accumulate and significantly exert potentially specific mechanisms of antitumor effects toward activation of precise cancer cell death pathways that can be explored. In this review, we aim to summarize the intracellular pathways of nanoparticles, highlighting the principles and state of their destructive effects in the subcellular structures as well as the current limitations of conventional therapeutic approaches. Next, we give an overview of subcellular performances and the fate of internalized nanoparticles under various organelle circumstances, particularly endosome or lysosome, mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus, by comprehensively emphasizing the unique mechanisms with a series of interesting reports. Moreover, intracellular transformation of the internalized nanoparticles, prominent outcome and potential affluence of these interdependent subcellular components in cancer therapy are emphasized. Finally, we conclude with perspectives with a focus on the contemporary challenges in their clinical applicability.

Engineered pH-responsive hydrazone-carboxylate complexes-encapsulated 2D matrices for cathepsin-mediated apoptosis in cancer.

Spurred by the current advancements in engineering various intelligent nanoparticle-based drug delivery systems, conjugation of drugs with the stimuli-responsive molecular switches has become one of the most efficient approaches to deliver a drug cargo in spatiotemporal controlled fashions. In this study, we fabricated an innovative pH-triggered hydrazone-carboxylate complex of doxorubicin (Dox), which was subsequently encapsulated in the layered double hydroxide (LDH) nanoparticles for effective cancer therapeutics. These two-dimensional (2D) biodegradable matrices efficiently delivered Dox by pH-triggered release in the acidic lysosomal environment and their subsequent escape to cytosol. Moreover, the delivered Dox molecules and high positively-charged surfaces of LDHs facilitated the cancer cell ablation via enhancing the cathepsins-mediated cell apoptosis assisted by free radical species generation. The critical advancements in the nanoparticle-based designs and substantial ablation of tumor cells through a free radical attack indicate that the designed pH-triggered drug composites can be used for efficient cancer therapeutics. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1184-1194, 2019.

High expression of the ANKRD49 protein is associated with progression and poor prognosis of gastric cancer.

BACKGROUND: Gastric cancer is one of the most common malignant tumours. Identifying novel genes that govern the development of gastric cancer will help to elucidate its molecular mechanisms and find novel biomarkers. METHODS: Expression of the ANKRD49 protein was assessed by immunohistochemical analysis of tissue microarrays containing 92 sets of human gastric cancer specimens with adjacent non-cancerous tissue. Associations between ANKRD49 levels and clinicopathological characteristics of the patient were investigated. The correlation between ANKRD49 expression and patient survival was analysed by the Kaplan-Meier method. RESULTS: The results revealed that the expression level of the ANKRD49 protein in gastric cancer was significantly upregulated and correlated with the tumour size, tumour-node-metastasis (TNM) stage, histological grade, depth of invasion, vessel invasion, lymph node metastasis and distant metastasis. The mean survival time of patients with low expression levels of ANKRD49 was significantly longer than that of patients with high expression levels of ANKRD49. Multivariate Cox regression analysis demonstrated that the ANKRD49 protein expression level was an independent prognostic indicator for the survival rate of patients with gastric cancer. CONCLUSION: The results of the present study highlighted an important role of the ANKRD49 protein in the progression of gastric cancer. The ANKRD49 protein could act as a potential biomarker for prognosis evaluation of gastric cancer and may be used as a molecular target for gastric cancer treatment.

Tuning the morphology and Fe/Ni ratio of a bimetallic Fe-Ni-S film supported on nickel foam for optimized electrolytic water splitting.

The surface composite and morphology of binary metal sulfides are the key for efficient overall water splitting. However, tuning the morphology and surface composition of binary metal sulfides in a facile way is still a challenge. Herein, binary Fe-Ni sulfides supported on nickel foam (FeNi-S/NF) with different morphology and composition ratio of Fe/Ni have been synthesized through a facile one-step electrodeposition assisted by liquidcrystaltemplate (LCT). The binary FeNi-S has improved activity and conductivity compared to single metal sulfides. LCT-assisted porous FeNi-S film composed of uniform nanospheres is obviously different from planar film electrodeposited in water solution. LCT-assisted FeNi-S nanospheres are covered by many interwoven nanosheets, implying more exposed active sites for water splitting. Furthermore, the different Fe/Ni ratios of FeNi-S/NF samples have been systematically studied to explore the influence of Fe-incorporation on intrinsic activity of FeNi-S/NF. And the sample with Fe/Ni ratio (3/1) demonstrates the best activity and excellent stability for overall water electrolysis. Therefore, our work provides a facile and controllable access to binary metal sulfides with excellent performances for overall water splitting.

Development of novel pH-sensitive thiolated chitosan/PMLA nanoparticles for amoxicillin delivery to treat Helicobacter pylori.

The cysteine conjugated chitosan/PMLA multifunctional nanoparticles were synthesized as targeted Nano-drug delivery system to eradicate Helicobacter pylori. Helicobacter pylori specifically express urea transport protein on its membrane to carrying urea to the cytoplasm urease to supply ammonia that protects bacteria in the acid environment of the stomach. The clinical suitability of topical antimicrobial agents is required to get rid of Helicobacter pylori inside the inflamed basal region. In this work, cysteine conjugated chitosan derivative, Cys-CS for their mucoadhesive and anticoagulant properties was designed and synthesized, for the preparation of multifunctional nanoparticles. The technique turned into optimized to prepare Cys-CS/PMLA nanoparticles for encapsulation of amoxicillin. The results showed that amoxicillin-Cys-CS/PMLA nanoparticles exhibit favorable pH-sensitive properties that could procrastinate the release of amoxicillin at gastric acid and allow the drug to deliver and target to Helicobacter pylori at its survival region efficiently. In comparison with unmodified amoxicillin-chitosan/PMLA nanoparticles, effective inhibition of Helicobacter pylori growth was observed for amoxicillin-Cys-CS/PMLA nanoparticles. These results indicate that the multifunctional amoxicillin-loaded nanoparticles have great potential for the effective treatment of Helicobacter pylori infection. They can also be used as pharmacologically powerful nanocarriers for oral targeted delivery of different therapeutic drugs to treat Helicobacter pylori.

Synthesis and evaluation of pH-sensitive, self-assembled chitosan-based nanoparticles as efficient doxorubicin carriers.

A novel pH-responsive polymer based on amphiphilic N-acetyl histidine and arginine-grafted chitosan was synthesized using N-acetyl histidine as hydrophobic segment and arginine as hydrophilic segment by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-mediated coupling reactions as anticancer drug delivery system for doxorubicin. The structure of the synthesized polymer was confirmed by Fourier transform infrared and 1H nuclear magnetic resonance analysis. Due to self-association behavior, N-acetyl histidine and arginine-grafted chitosan structured nanoparticles with in size range of 204 nm. N-acetyl histidine and arginine-grafted chitosan with different substitution degree of N-acetyl histidine were initially prepared and characterized. The critical micelle concentration decreased with increasing substitution degree of N-acetyl histidine. Furthermore, N-acetyl histidine and arginine-grafted chitosan nanoparticles exhibited an acidic pH-triggered aggregation and disassembling nature. The doxorubicin-encapsulated nanoparticles based on synthesized conjugate ( N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles) showed a sustained drug release pattern, which could be hastened under acidic pH conditions but delayed with increasing substitution degree of N-acetyl histidine. Anticancer effects demonstrated that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles could suppress both sensitive and resistant human breast tumor cell line (MCF-7) efficiently in a dose- and time-dependent pattern. Confocal microscopy results evidenced increased cellular uptake and enhanced retention of the synthesized nanoparticles in drug-resistant cells demonstrating better efficacy of nanoparticles over native doxorubicin. These results suggest that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles might be promising carriers for delivery of hydrophobic drug doxorubicin against drug-resistant tumors.

Overcoming Multidrug Resistance through the Synergistic Effects of Hierarchical pH-Sensitive, ROS-Generating Nanoreactors.

Recently, multidrug resistance (MDR) has become a major clinical chemotherapeutic burden that robustly diminishes the intracellular drug levels through various mechanisms. To overcome the doxorubicin (Dox) resistance in tumor cells, we designed a hierarchical nanohybrid system possessing copper-substituted mesoporous silica nanoparticles (Cu-MSNs). Further, Dox was conjugated to copper metal in the Cu-MSNs framework through a pH-sensitive coordination link, which is acutely sensitive to the tumor acidic environment (pH 5.0-6.0). In the end, the nanocarrier was coated with D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), a P-gp inhibitor-entrenched compact liposome net for obstructing the drug efflux pump. Copper ions in the framework synergize the antitumor activity of Dox by enhancing the intracellular reactive oxygen species (ROS) levels through a Fenton-like reaction-mediated conversion of hydrogen peroxide. Furthermore, intracellularly generated ROS triggered the apoptosis by reducing the cellular as well as mitochondrial membrane integrity in MDR cells, which was confirmed by the mitochondrial membrane potential (MMP) measurement. The advancement of the design and critical improvement of cytotoxic properties through free radical attack demonstrate that the proposed hierarchical design can devastate the MDR for efficient cancer treatment.