10-nm Nanoparticles Research Articles

Organophosphate Detoxification and Acetylcholinesterase Reactivation Triggered by Zeolitic Imidazolate Framework Structural Degradation.

Organophosphate (OP) toxicity is related to inhibition of acetylcholinesterase (AChE) activity, which plays a key role in the neurotransmission process. In this work, we report the ability of different zinc zeolitic imidazolate frameworks (ZIFs) to behave as potential antidotes against OP poisoning. The Zn-L coordination bond (L = purine, benzimidazole, imidazole, or 2-methylimidazole) is sensitive to the G-type nerve agent model compounds diisopropylfluorophosphate (DIFP) and diisopropylchlorophosphate, leading to P-X (X = F or Cl) bond breakdown into nontoxic diisopropylphosphate. P-X hydrolysis is accompanied by ZIF structural degradation (Zn-imidazolate bond hydrolysis), with the concomitant release of the imidazolate linkers and zinc ions representing up to 95% of ZIF particle dissolution. The delivered imidazolate nucleophilic attack on the OP@AChE adduct gives rise to the recovery of AChE enzymatic function. P-X bond breakdown, ZIF structural degradation, and AChE reactivation are dependent on imidazolate linker nucleophilicity, framework topology, and particle size. The best performance is obtained for 20 nm nanoparticles (NPs) of Zn(2-methylimidazolate)2 (sod ZIF-8) exhibiting a DIFP degradation half-life of 2.6 min and full recovery of AChE activity within 1 h. 20 nm sod ZIF-8 NPs are not neurotoxic, as proven by in vitro neuroblastoma cell culture viability tests.

Iron oxide/graphene oxide nanocomposite synthesis using atmospheric cold plasma.

Herein, we demonstrate the use of an atmospheric pressure plasma with a Dielectric Barrier Discharge (DBD) for the synthesis of FeOx nanoparticles with a simultaneous formation of graphene oxide domains at low substrate temperature. For that, the interaction of the plasma to control good decomposition of the Fe precursor is essential and this is demonstrated by FTIR analyses. Thanks to a fine tuning of the plasma conditions, a homogeneous spatial distribution around 5 nm nanoparticles (NPs) was obtained, whereas without plasma, in the same configuration of the process, a heterogeneity regarding size and shape for the NPs was obtained. The Raman spectrum of the plasma deposit confirmed the presence of graphene oxide as the characteristic G and D bands were observed with I(D)/I(G) = 0.92. Thanks to optical emission spectroscopy (OES) measurements, it is proposed that the carbon deposition on FeOx nanoparticles is produced on the near plasma post discharge. XPS studies showed that the main contribution of iron was in Fe2+ form, corresponding to the FeO phase. No metallic Fe or carbide were detected. As there are many studies reporting the synergetic effect of FeOx NPs and graphene oxide, we believe that this new one-step simultaneous synthesis method may be of high interest for applications requiring direct deposition on temperature labile substrates such as polymers.

Liquid foams with a lifetime of several days co-stabilized by monodisperse protein nanoparticles and mechanically stable starch nanocrystals

Liquid foams stabilized by protein nanoparticles generally have a lifetime less than several hours because of poor interface and unavoidable coalescence, which strictly limits their applications in, e.g., coffee toppings and milk shakes. In this study, stable foams with a lifetime of several days were prepared by protein nanoparticle-starch nanocrystal (SNC) complexes. The nanoparticles of rice proteins (RPs) or rice bran proteins (RBPs) were prepared by neutralization of their alkaline solutions by cationic exchange resins (CERs) that displace Na+ by releasing H+, leading to the formation of monodisperse, 20-nm nanoparticles facilitating diffusion to the water-air interface. The complexes were assembled by simply mixing proteins with SNCs, affording the formation of quite dispersed network structures (RP@SNCs or RBP@SNCs). During whipping, the protein nanoparticles performed as the diffusion initiators from the continuous phase to the biphasic interface, whereas the SNCs stabilized the interface and functioned as the spacers preventing the approaching of adjacent bubbles in the continuous phase. Moreover, RPs and RBPs had different affinities to SNCs, resulting in foams of varied stabilities. Our study represented a compelling example of structuring stable foams taking joint advantages of diffusion behaviors of protein nanoparticles and biphasic stabilization of SNCs.

Ice Composites Strengthened by Organic and Inorganic Nanoparticles

Extensive development of the Arctic, rich in various natural resources, requires a lot of cheap ecologically safe construction materials preferably using local renewable sources. Ice being easily available in regions with a cold climate meets all the above criteria but has low strength, high fragility and a tendency to creep. Known strengthening techniques using macroscopic and microfiber additives have many drawbacks. This paper describes a new approach to ice strengthening by adding organic or inorganic 50–100 nm nanoparticles (NPs) to the water to be frozen and presents experimental results and possible mechanisms analysis of polycrystalline ice strengthening using NPs. Cellulose and silica NPs have been tested as typical representatives of such additives. Both are hydrophilic, ecologically safe, widespread, cheap and can be produced from local renewable raw materials. It is shown that the addition of 0.01 to 5 wt.% of NPs results in a reduction of ice composite average grain size by a factor of 5.3 ± 0.7 and an increase of its compression strength by a factor of 2.5 ± 0.3. The highest sensitivity of ice strength to NPs concentration is between 0.1 and 1 wt.%. In this concentration range, the increase in strength is reversely proportional to the square root of the average grain size. Experimental data fit Griffith’s relation better than Hall–Petch, so ice strength is limited by cracks with the length proportional to average grain size.

Surface Adsorbed Hydroxyl: A Double‐Edged Sword in Electrochemical CO2 Reduction over Oxide‐Derived Copper

AbstractOxide‐derived Cu (OD−Cu) featured with surface located sub‐20 nm nanoparticles (NPs) created via surface structure reconstruction was developed for electrochemical CO2 reduction (ECO2RR). With surface adsorbed hydroxyls (OHad) identified during ECO2RR, it is realized that OHad, sterically confined and adsorbed at OD−Cu by surface located sub‐20 nm NPs, should be determinative to the multi‐carbon (C2) product selectivity. In situ spectral investigations and theoretical calculations reveal that OHad favors the adsorption of low‐frequency *CO with weak C≡O bonds and strengthens the *CO binding at OD−Cu surface, promoting *CO dimerization and then selective C2 production. However, excessive OHad would inhibit selective C2 production by occupying active sites and facilitating competitive H2 evolution. In a flow cell, stable C2 production with high selectivity of ∼60 % at −200 mA cm−2 could be achieved over OD−Cu, with adsorption of OHad well steered in the fast flowing electrolyte.

Surface Adsorbed Hydroxyl: A Double-Edged Sword in Electrochemical CO2 Reduction over Oxide-Derived Copper.

Oxide-derived Cu (OD-Cu) featured with surface located sub-20 nm nanoparticles (NPs) created via surface structure reconstruction was developed for electrochemical CO2 reduction (ECO2 RR). With surface adsorbed hydroxyls (OHad ) identified during ECO2 RR, it is realized that OHad , sterically confined and adsorbed at OD-Cu by surface located sub-20 nm NPs, should be determinative to the multi-carbon (C2 ) product selectivity. In situ spectral investigations and theoretical calculations reveal that OHad favors the adsorption of low-frequency *CO with weak C≡O bonds and strengthens the *CO binding at OD-Cu surface, promoting *CO dimerization and then selective C2 production. However, excessive OHad would inhibit selective C2 production by occupying active sites and facilitating competitive H2 evolution. In a flow cell, stable C2 production with high selectivity of ∼60 % at -200 mA cm-2 could be achieved over OD-Cu, with adsorption of OHad well steered in the fast flowing electrolyte.

Fluorophore-tagged poly(ʟ-Lysine) block copolymer nano-assemblies for real-time visualization and antimicrobial activity

Development of self-reporting polymers having dual-action of membrane disruption for antimicrobial activity and simultaneous visualization and quantification by microscopic imaging techniques are urgently required for early detection and therapeutics. Here, we report a new series of self-reporting coumarin fluorophore-tagged polypeptides based on PEG-block-poly(ʟ-lysine) copolymers via ring opening polymerization (ROP) strategy. For this purpose, NHC catalyzed controlled ROP was optimised for ε-Cbz-ʟ-lysine NCA monomer to make desired chain length polypeptides. The resultant cationic polymer was self-assembled into 100 ± 15 nm nanoparticles (NP) having Zeta potentials of +25 to +44 mV associated with strong blue-emission in aqueous medium. The antimicrobial action of these polymers was tested in E. coli by colony suspension method and their MIC90 values were obtained to be 1 × 10−4 to 3 × 10−4 g/mL. Real-time confocal microscopic imaging enabled the direct visualization of the fluorescent peptide NP action on the E. coli membrane, and propidium iodide co-staining assay further established the membrane pore formation mechanism for their antimicrobial activity. In vitro cytotoxicity and cellular uptake studies in MCF-7 breast cancer cell lines revealed that the fluorescent polypeptide NP were readily internalized at the cellular level, and they were also found to be nontoxic to cells up to 80 μg/mL and showed minimal haemolysis to RBCs at their MIC concentration which further established their high biocompatibility as suitable biomaterials.

Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models.

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.

Aqueous TiO2 Nanoparticles React by Proton-Coupled Electron Transfer.

Redox reactions of aqueous colloidal TiO2 4 nm nanoparticles (NPs) have been examined, including both citrate-capped and uncapped NPs (c-TiO2 and uc-TiO2). Photoreduction gave stable blue colloidal c-TiO2R NPs with 10-60 electrons per particle. Equilibration of these reduced NPs with soluble redox reagents such as methylviologen (MV2+) provided measurements of the colloid reduction potential as a function of pH. The potentials of c-TiO2 from pH 2-9 varied linearly with pH, with a slope of -60 ± 5 mV/pH. Estimates of the potential at pH 12 were consistent with extrapolating that line to high pH. The reduction potentials did not correlate with the zeta potentials (ζ) or the surface charge of the NPs across this pH range. Similar reduction potentials were observed for c- and uc-TiO2 at low pH even though they have quite different ζ potentials. These results show that the common surface-charging explanation of the pH dependence is not tenable in these systems. Oxidation of reduced c-TiO2R with the electron-transfer oxidant potassium triiodide (KI3) occurred with a significant drop in pH, showing that protons were released when the electrons were removed from the NPs. Smaller pH drops were observed for the proton-coupled electron transfer (PCET) reagents O2 (air) and 4-MeO-TEMPO (4-methoxy-2,2,6,6-tetramethylpiperine-1-oxy radical). The difference in the number of protons released with KI3 vs O2 and 4-MeO-TEMPO was roughly one proton per electron removed. Thus, the thermodynamically preferred reactivity of these colloidal TiO2 NPs is PCET over the pH 2-13 range studied. The measured redox potentials refer to the chemical process TiO2 + H+ + e- → TiO2·e-,H+; and therefore they do not correspond with an electronic energy such as a conduction band edge or flat band potential. The 1e-/1H+ stoichiometry means that the TiO2 reduction potentials correspond to a TiO2-H bond dissociation free energy (BDFE), determined to be 49 ± 2 kcal mol-1. The PCET description is consistent with the pH dependence of E(TiO2/TiO2·e-,H+), the release of protons upon oxidation, the lack of correlation with ζ potentials, the similarity of capped and uncapped NPs, and the small change in the potential and BDFE from the first to the last electron/proton pair (H atom) removed. This behavior is suggested to be the norm for redox-active oxide/water interfaces.

Controlling Droplet Marangoni Flows to Improve Microscopy-Based TB Diagnosis.

In developing countries, the most common diagnostic method for tuberculosis (TB) is microscopic examination sputum smears. Current assessment requires time-intensive inspection across the microscope slide area, and this contributes to its poor diagnostic sensitivity of ≈50%. Spatially concentrating TB bacteria in a smaller area is one potential approach to improve visual detection and potentially increase sensitivity. We hypothesized that a combination of magnetic concentration and induced droplet Marangoni flow would spatially concentrate Mycobacterium tuberculosis on the slide surface by preferential deposition of beads and TB–bead complexes in the center of an evaporating droplet. To this end, slide substrate and droplet solvent thermal conductivities and solvent surface tension, variables known to impact microfluidic flow patterns in evaporating droplets, were varied to select the most appropriate slide surface coating. Optimization in a model system used goniometry, optical coherence tomography, and microscope images of the final deposition pattern to observe the droplet flows and maximize central deposition of 1 μm fluorescent polystyrene particles and 200 nm nanoparticles (NPs) in 2 μL droplets. Rain-X® polysiloxane glass coating was identified as the best substrate material, with a PBS-Tween droplet solvent. The use of smaller, 200 nm magnetic NPs instead of larger 1 μm beads allowed for bright field imaging of bacteria. Using these optimized components, we compared standard smear methods to the Marangoni-based spatial concentration system, which was paired with magnetic enrichment using iron oxide NPs, isolating M. bovis BCG (BCG) from samples containing 0 and 103 to 106 bacilli/mL. Compared to standard smear preparation, paired analysis demonstrated a combined volumetric and spatial sample enrichment of 100-fold. With further refinement, this magnetic/Marangoni flow concentration approach is expected to improve whole-pathogen microscopy-based diagnosis of TB and other infectious diseases.

Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases.

Neurons within the tumor microenvironment promote cancer progression; thus, their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer cross-talk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration, and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer cell viability. In vivo, bupivacaine-loaded nanoparticles intravenously administered suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

Deformable microparticles for shuttling nanoparticles to the vascular wall.

Vascular-targeted drug carriers must localize to the wall (i.e., marginate) and adhere to a diseased endothelium to achieve clinical utility. The particle size has been reported as a critical physical property prescribing particle margination in vitro and in vivo blood flows. Different transport process steps yield conflicting requirements-microparticles are optimal for margination, but nanoparticles are better for intracellular or tissue delivery. Here, we evaluate deformable hydrogel microparticles as carriers for transporting nanoparticles to a diseased vascular wall. Depending on microparticle modulus, nanoparticle-loaded poly(ethylene glycol)-based hydrogel microparticles delivered significantly more 50-nm nanoparticles to the vessel wall than freely injected nanoparticles alone, resulting in >3000% delivery increase. This work demonstrates the benefit of optimizing microparticles' efficient margination to enhance nanocarriers' transport to the vascular wall.

Co-encapsulation of collagenase type I and silibinin in chondroitin sulfate coated multilayered nanoparticles for targeted treatment of liver fibrosis

Components of the extracellular matrix (ECM) are overexpressed in fibrotic liver. Collagen is the main component of the liver fibrosis stroma. Here we demonstrate that chondroitin sulfate coated multilayered 50-nm nanoparticles encapsulating collagenase and silibinin (COL + SLB-MLPs) break down the dense collagen stroma, while silibinin inhibits activated hepatic stellate cells. The nanoparticles were taken up to a much greater extent by hepatic stellate cells than by normal hepatocytes, and they down-regulated production of type I collagen. In addition, chondroitin sulfate protected the collagenase from premature deactivation. COL + SLB-MLPs were delivered to the cirrhotic liver, and the collagenase and silibinin synergistically inhibited fibrosis in mice. Immunofluorescence staining of liver tissues revealed that CD44, mediated by chondroitin sulfate, delivered the nanoparticles to hepatic stellate cells. This strategy holds promise for degrading extracellular stroma and thereby facilitating drug penetration into fibrotic liver and related diseases such as liver cirrhosis and liver cancer.

Scavenger receptor MARCO contributes to cellular internalization of exosomes by dynamin-dependent endocytosis and macropinocytosis

Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor class-A protein that is expressed on the cell surface of macrophages. MARCO mediates binding and ingestion of unopsonized environmental particles, including nano-sized materials. Exosomes are cell-derived, nano-sized vesicles (40–150 nm) that can contain lipids, RNA, DNA, and various proteins. Exosomes play an essential role in cell-to-cell communication via body fluids. However, mechanisms for the recognition and internalization of exosomes by recipient cells remain poorly characterized. In this study, cellular association of serum-derived fluorescent exosomes and 20-nm fluorescent nanoparticles (positive control) was compared between MARCO-expressing (CHO-MARCO) and control (CHO-CT) CHO-K1 cells to examine whether MARCO expression by recipient cells mediates the cellular uptake of exosomes and environmental nanoparticles. Fluorescence microscopic studies and quantitative analyses revealed that the cellular associations of both exosomes and 20-nm nanoparticles were greater in CHO-MARCO cells than in CHO-CT cells. Exosomes and nanoparticles colocalized with green fluorescent protein (GFP)-MARCO in cells transfected with GFP-MARCO-encoding constructs . Furthermore, inhibitory studies showed that actin reorganization and dynamin are involved in the MARCO-mediated cellular internalization of exosomes. These results indicated that MARCO plays a role in the uptake of exosomes.

Delivery of Antisense DNA into Pathogenic Parasite Trypanosoma cruzi Using Virus-Like Protein-Based Nanoparticles.

Trypanosoma cruzi, which causes Chagas disease, is one of the most lacerating parasites in terms of health and social impacts. New approaches for its study and treatment are urgently needed since in more than 50 years only two drugs have been approved. Genetic approaches based on antisense oligonucleotides (AONs) are promising; however, to harness their full potential the development of effective carriers is paramount. Here, we report the use of an engineered virus-like protein C-BK12 to transfect AONs into T. cruzi. Using gel electrophoresis, Dynamic Light Scattering, and atomic force microscopy, we found that C-BK12 binds AONs and forms 10-25 nm nanoparticles (NPs), which are very stable when incubated in biological media, only releasing up to 25% of AON. Fluorescence microscopy and qPCR revealed that the NPs successfully delivered AONs into epimastigotes and reduced the expression of a target gene down to 68%. Importantly, the protein did not show cytotoxicity. The combination of high stability and capability to transfect and knock down gene expression without causing cell damage and death makes the protein C-BK12 a promising starting point for the further development of safe and effective carriers to deliver AONs into T. cruzi for biological studies.

Formation of irregular morphology on nanostructured surface by gas cluster ion beam

Ar1000 cluster ion beam was used to fabricate irregular structures of a micrometer scale on the surface of pressed Si powder of 60 nm nanoparticles (NPs). The average density of the target material played an important role in the surface features formation. The samples with lower average density, i.e. with larger distance between adjacent NPs demonstrated more developed surface morphology, which implied an importance of the degree of freedom of NP and its beam induced mobility in formation of the surface features. At higher average density a process of particle erosion was accompanied by the debris formation, which filled the gaps between the NPs, blocked the particle mobility, and, eventually, resulted in conventional smoothing effect.

Optimization of the interaction of graphene quantum dots with lipase for biological applications.

Graphene quantum dots (GQDs) are known as emerging sub-10 nm nanoparticles (NPs), which are in fact few-layered pieces of graphene, capable of emitting blue fluorescence, when exposed to 360 nm UV light. Understanding the details of the interaction between GQDs and lipase can serve as a critical step for improving the biological outcome of GQD-derived drug-delivery and diagnosis systems. The interaction occurs in the form of surface adsorption, which can subsequently influence the physicochemical properties of both the NP and the protein. Hence, a systematic approach was taken here to optimize the GQDs' synthesis conditions in order to achieve the highest possible quantum yield (QY). Furthermore, to understands the influence of the interaction of GQDs and lipase, on both the activity of lipase and the emission intensity of GQDs, various incubation conditions were tested to achieve optimized conditions over central composite design algorithm by Design-Expert®, using response surface methodology. The results show that the GQDs fabricated by thermal decomposition of citric acid at 160°C, with a heating duration of 55 min, obtain almost three times higher QY than the highest values reported previously. The best enzymatic activity after the formation of the hard corona, as well as the highest fluorescent emission, were achieved at GQD-to-enzyme ratios within the rage of 23-25%, at temperatures between 41 and 42°C, for 6-8 min. In the aforementioned condition, the enzyme retains 91-95% of its activity and the NP preserves about 80-82% of its fluorescence intensity after incubation.

Highly Efficient AuPd Catalyst for Synthesizing Polybenzoxazole with Controlled Polymerization

Summary Using nanoparticles (NPs) to catalyze chemical reactions for the formation of functional polymers with controlled polymerization is an important field of chemical research. In this article, we report an AuPd NP system as an active and stable catalyst to catalyze one-pot reaction of formic acid, 1,5-diisopropoxy-2,4-dinitrobenzene, and terephthaldehyde, leading to the controlled polymerization and the formation of polybenzoxazole (PBO) (Mw = 3.6 kDa). The one-pot reaction is AuPd NP size and composition dependent, and 8-nm Au39Pd61 NPs are the best catalyst for the polymerization. The highly pure PBO shows excellent thermal stability up to 600°C and improved chemical and mechanical stability under challenging environmental conditions compared with commercial PBO (Zylon, Mw = 40 kDa). The reported NP-catalyzed one-pot reaction to polymerization is not limited to the formation of PBO but can be extended as a general approach to rigid polymers that are important for ballistic fiber, anti-flame, and smart-textile applications.

In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

Pro-Nifuroxazide Self-Assembly Leads to Triggerable Nanomedicine for Anti-cancer Therapy.

Transcription factor STAT3 has been shown to regulate genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of great biological significance. However, many small-molecule agents with potential effects through STAT3 modulation in cancer therapy lack aqueous solubility and high off-target toxicity, hence impeding efficient bioavailability and activity. This work, for the first time, reports a prodrug-based strategy for selective and safer delivery of STAT3 inhibitors designed toward metastatic and drug-resistant breast cancer. We have synthesized a novel lipase-labile SN-2 phospholipid prodrug from a clinically investigated STAT3 inhibitor, nifuroxazide (Pro-nifuroxazide), which can be regioselectively cleaved by the membrane-abundant enzymes in cancer cells. Pro-nifuroxazide self-assembled to sub 20 nm nanoparticles (NPs), and the cytotoxic ability was screened in ER(+)-MCF-7 and ER(-)-MD-MB231 cells at 48-72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide proliferation assay. Results indicated that Pro-nifuroxazide NPs are multifold more effective toward inhibiting cancer cells in a time-dependent manner compared to parent nifuroxazide. A remarkable improvement in the local concentration of drugs to as high as ∼240 fold when assembled into NPs is presumably the reason for this functional improvement. We also introduced molecular dynamics simulations to generate Pro-nifuroxazide nano-assembly, as a model assembly from triggerable anti-cancer drugs, to provide molecular insights correlating physicochemical and anti-cancer properties. In silico properties of Pro-nifuroxazide including size, chemistry of NPs and membrane interactions with individual molecules could be validated by in vitro functional activities in cells of breast cancer origin. The in vivo anti-cancer efficiencies of Pro-nifuroxazide NPs in nude mice xenografts with MCF-7 revealed remarkable growth inhibition of as high as 400%. Histopathological analysis corroborated these findings to show significantly high nuclear fragmentation and retracted cytoplasm. Immunostaining on tumor section demonstrated a significantly lower level of pSTAT-3 by Pro-nifuroxazide NP treatment, establishing the inhibition of STAT-3 phosphorylation. Our strategy for the first time proposes a translatable prodrug agent self-assembled into NPs and demonstrates remarkable enhancement in IC50, induced apoptosis, and reduced cancer cell population through STAT-3 inhibition via reduced phosphorylation.