Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study.

Background: Epilepsy is one of the most prevalent serious brain disorders globally, impacting over 70 million individuals. Observational studies have increasingly recognized the impact of plasma lipidome on epilepsy. However, establishing a direct causal link between plasma lipidome and epilepsy remains elusive due to inherent confounders and the complexities of reverse causality. This study aims to investigate the causal relationship between specific plasma lipidome and epilepsy, along with their intermediary mediators. Methods: We conducted a two-sample Mendelian randomization (MR) and mediation MR analysis to evaluate the causal effects of 179 plasma lipidomes and epilepsy, with a focus on the inflammatory cytokine as a potential mediator based on the genome-wide association study. The primary methodological approach utilized inverse variance weighting, complemented by a range of other estimators. A set of sensitivity analyses, including Cochran's Q test, I 2 statistics, MR-Egger intercept test, MR-PRESSO global test and leave-one-out sensitivity analyses was performed to assess the robustness, heterogeneity and horizontal pleiotropy of results. Results: Our findings revealed a positive correlation between Phosphatidylcholine (18:1_18:1) levels with epilepsy risk (OR = 1.105, 95% CI: 1.036-1.178, p = 0.002). Notably, our mediation MR results propose Tumor necrosis factor ligand superfamily member 12 levels (TNFSF12) as a mediator of the relationship between Phosphatidylcholine (18,1_18:1) levels and epilepsy risk, explaining a mediation proportion of 4.58% [mediation effect: (b = 0.00455, 95% CI: -0.00120-0.01030), Z = 1.552]. Conclusion: Our research confirms a genetic causal relationship between Phosphatidylcholine (18:1_18:1) levels and epilepsy, emphasizing the potential mediating role of TNFSF12 and provide valuable insights for future clinical investigations into epilepsy.

Bioorthogonal Cu Single-Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy.

Single-atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in-depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding-embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu-C3 coordinated configuration. To enhance the tumor-specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off-target toxicity but also possesses exceptional ultrahigh catalase-, oxidase-, peroxidase-like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO's remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme-like behavior and physiological mechanism of action of SAzymes.

Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H2S Gas and Photodynamic Immunotherapy.

Hydrogen sulfide (H2S) has shown promise for gas therapy. However, it is still controversial whether H2S can remodel the tumor microenvironment (TME) and induce robust antitumor immunity. Here, a tumor-targeting and TME-responsive "smart" lipid nanoparticle (1-JK-PS-FA) is presented, which is capable of delivering and releasing H2S specifically in tumor tissues for on-demand H2S gas and photodynamic immunotherapy. 1-JK-PS-FA enables a burst release of H2S in the acidic TME, which promptly reduces the embedded organic electrochromic materials and consequently switches on near-infrared fluorescence and photodynamic activity. Furthermore, we found that high levels of H2S can reprogram the TME by reducing tumor interstitial fluid pressure, promoting angiogenesis, increasing vascular permeability, ameliorating hypoxia, and reducing immunosuppressive conditions. This leads to increased tumor uptake of 1-JK-PS-FA, thereby enhancing PDT efficacy and eliciting strong immunogenic cell death during 808 nm laser irradiation. Therefore, 1-JK-PS-FA permits synergistic H2S gas and photodynamic immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence. This work showcases the capacity of H2S to reprogram the TME to enhance H2S gas and immunotherapy.

Ratiometric Near-Infrared Fluorescence Liposome Nanoprobe for H2S Detection In Vivo.

Accurate detection of H2S is crucial to understanding the occurrence and development of H2S-related diseases. However, the accurate and sensitive detection of H2S in vivo still faces great challenges due to the characteristics of H2S diffusion and short half-life. Herein, we report a H2S-activatable ratiometric near-infrared (NIR) fluorescence liposome nanoprobe HS-CG by the thin-film hydration method. HS-CG shows "always on" fluorescence signal at 816 nm and low fluorescence signal at 728 nm; the NIR fluorescence ratio between 728 and 816 nm (F728/F816) is low. Upon reaction with H2S, the fluorescence at 728 nm could be more rapidly turned on due to strong electrostatic interaction between enriched HS- and positively charged 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC) doped in the liposome nanoprobe HS-CG, resulting in a large enhancement of F728/F816, which allows for sensitive visualization of the tumor H2S levels in vivo. This study demonstrates that this strategy of electrostatic adsorption between HS- and positively charged molecules provides a new way to enhance the reaction rate of the probe and H2S, thus serving as an effective platform for improving the sensitivity of imaging.

Controlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics.

Temporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly.

Tumor-targeted and stimuli-activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor-targeted and redox-activatable nanosensitizers (1-NPs) for sono-photodynamic immunotherapy of tumors by molecular co-assembly and redox-controlled disassembly. 1-NPs show a high longitudinal relaxivity (r1 =18.7±0.3 mM-1 s-1 ), but "off" dual fluorescence (FL) emission (at 547 and 672 nm), "off" sono-photodynamic therapy and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1-NPs rapidly disassemble and remotely release small molecules 2-Gd, Zn-PPA-SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono-photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1-NPs are effective for bimodal FL and magnetic resonance (MR) imaging-guided sono-photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671-nm laser irradiation.

A Ratiometric Photoacoustic Probe with a Reversible Response to Hydrogen Sulfide and Hydroxyl Radicals for Dynamic Imaging of Liver Inflammation.

Reversible imaging probes that allow for the dynamic visualization of the redox cycle between hydroxyl radical (⋅OH) and hydrogen sulfide (H2 S) are vital to probe the redox imbalance-involved pathological process in vivo. Herein, we report a reversible ratiometric photoacoustic (PA) imaging nanoprobe (1-PAIN) for the real-time imaging of ⋅OH/H2 S redox cycle in vivo. 1-PAIN displays a low PA ratio between 690 and 825 nm (PA690 /PA825 ), which significantly increases by ≈5-fold upon oxidation by ⋅OH, and is switched back to the initially low PA690 /PA825 value upon reduction by H2 S. 1-PAIN could dynamically report on the hepatic ⋅OH production in mice during the lipopolysaccharide (LPS)-induced liver inflammation process, and visualize hepatic H2 S generation during the N-acetyl cysteine (NAC)-induced anti-inflammation process. 1-PAIN can act as a useful tool to probe the redox state in living biology, beneficial for the study of redox imbalance-related diseases.

A supramolecular photosensitizer derived from an Arene-Ru(II) complex self-assembly for NIR activated photodynamic and photothermal therapy.

Effective photosensitizers are of particular importance for the widespread clinical utilization of phototherapy. However, conventional photosensitizers are usually plagued by short-wavelength absorption, inadequate photostability, low reactive oxygen species (ROS) quantum yields, and aggregation-caused ROS quenching. Here, we report a near-infrared (NIR)-supramolecular photosensitizer (RuDA) via self-assembly of an organometallic Ru(II)-arene complex in aqueous solution. RuDA can generate singlet oxygen (1O2) only in aggregate state, showing distinct aggregation-induced 1O2 generation behavior due to the greatly increased singlet-triplet intersystem crossing process. Upon 808 nm laser irradiation, RuDA with excellent photostability displays efficient 1O2 and heat generation in a 1O2 quantum yield of 16.4% (FDA-approved indocyanine green: ΦΔ = 0.2%) together with high photothermal conversion efficiency of 24.2% (commercial gold nanorods: 21.0%, gold nanoshells: 13.0%). In addition, RuDA-NPs with good biocompatibility can be preferably accumulated at tumor sites, inducing significant tumor regression with a 95.2% tumor volume reduction in vivo during photodynamic therapy. This aggregation enhanced photodynamic therapy provides a strategy for the design of photosensitizers with promising photophysical and photochemical characteristics.

An Activatable Afterglow/MRI Bimodal Nanoprobe with Fast Response to H2 S for In Vivo Imaging of Acute Hepatitis.

Accurate detection of hepatic hydrogen sulfide (H2 S) to monitor H2 S-related enzymes' activity is critical for acute hepatitis diagnosis, but remains a challenge due to the dynamic and transient nature of H2 S. Here, we report a H2 S-activatable near-infrared afterglow/MRI bimodal probe F1-GdNP, which shows an "always-on" MRI signal and "off-on" afterglow signal toward H2 S. F1-GdNP shows fast response, high sensitivity and specificity toward H2 S, permitting afterglow imaging of H2 S and evaluation of cystathionine γ-lyase (CSE)'s activity in living mice. We further employ the high spatial-resolution MRI signal of F1-GdNP to track its delivery and accumulation in liver. Importantly, F1-GdNP offers a high signal-to-background ratio (SBR=86.2±12.0) to sensitively report on the increased hepatic H2 S level in the acute hepatitis mice via afterglow imaging, which correlated well with the upregulated CSE activity in the liver, showcasing the good potential of F1-GdNP for monitoring of acute hepatitis process in vivo.

Generation of hydroxyl radical-activatable ratiometric near-infrared bimodal probes for early monitoring of tumor response to therapy.

Tumor response to radiotherapy or ferroptosis is closely related to hydroxyl radical (•OH) production. Noninvasive imaging of •OH fluctuation in tumors can allow early monitoring of response to therapy, but is challenging. Here, we report the optimization of a diene electrochromic material (1-Br-Et) as a •OH-responsive chromophore, and use it to develop a near-infrared ratiometric fluorescent and photoacoustic (FL/PA) bimodal probe for in vivo imaging of •OH. The probe displays a large FL ratio between 780 and 1113 nm (FL780/FL1113), but a small PA ratio between 755 and 905 nm (PA755/PA905). Oxidation of 1-Br-Et by •OH decreases the FL780/FL1113 while concurrently increasing the PA755/PA905, allowing the reliable monitoring of •OH production in tumors undergoing erastin-induced ferroptosis or radiotherapy.

Degradable FeCuS-Lipid Nanoparticles Confer Ultrasound-Activated CO Release and O2-Independent Radical Production for Synergistic Therapy.

Ultrasound (US)-activated nanoagents capable of producing cytotoxic species have been promising for the treatment of deep-seated tumors; however, poor tumor uptake and insufficient generation of cytotoxic agents have largely limited their therapeutic efficacy in vivo. Herein, we report a hybrid FeCuS-lipid nanoparticle (AIBA@FeCuS-FeCO) by amphiphilic lipids-assisted emulsion of a free radical initiator (AIBA), a radical-sensitive CO donor (Fe3(CO)12), and radical-degradable FeCuS nanodisks for US-activated synergistic therapy of deep-located orthotopic gastric tumors in living mice. Upon US irradiation, AIBA@FeCuS-FeCO could be degraded and release cytotoxic AIBA radicals, CO, Fe2+, and Cu2+, allowing us to (1) enhance tumor uptake of AIBA@FeCuS-FeCO through CO-mediated vasodilation, (2) promote hydroxyl radical production and induce tumor ferroptosis via intracellular accumulation of Fe2+/Cu2+, and (3) kill tumor cells. Moreover, the subsequent administration of disulfiram (DSF) could further chelate with the liberated Cu2+, yielding toxic bis(N,N-diethyl dithiocarbamato)copper(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.

Ratiometric Imaging of MMP-2 Activity Facilitates Tumor Detection Using Activatable Near-Infrared Fluorescent Semiconducting Polymer Nanoparticles.

Enzyme-activatable ratiometric near-infrared (NIR) fluorescent probes enabling noninvasive imaging of enzyme activity in vivo are promising for biomedical research; however, such probes with ratiometric fluorescence emissions both in NIR window under a single NIR light excitation are largely unexplored. Here, a quenched NIR fluorophore of Cy5.5 is integrated with NIR fluorescent poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT)-based semiconducting polymer nanoparticles (SPNs), and an αv ß3 integrin-targeting and matrix metalloproteinase-2 (MMP-2)-activatable ratiometric fluorescent probe (SPN-MMP-RGD) is developed. Under excitation at 660 nm, SPN-MMP-RGD shows "always-on" fluorescence of PCPDTBT (830 nm) and activatable fluorescence of Cy5.5 (690 nm) toward MMP-2, affording a remarkable ≈176-fold enhancement in fluorescence intensity ratio between 690 and 830 nm (I690 /I830 ) for sensitive detection of MMP-2 activity in vitro and in tumor cells. By virtue of ratiometric fluorescence imaging independently of probe's concentration, SPN-MMP-RGD can not only accurately report on MMP-2 levels regarding different tumor sizes, but also noninvasively delineate MMP-2-positive tiny gastric tumors metastasis in vivo. The authors' study reveals the potential of SPN-MMP-RGD for ratiometric fluorescence imaging of MMP-2 activity via combining two independent NIR fluorophores, which can be amenable for the design of other enzyme-activatable ratiometric NIR fluorescent probes for reliable in vivo imaging.

H2S-activatable near-infrared afterglow luminescent probes for sensitive molecular imaging in vivo.

Afterglow luminescent probes with high signal-to-background ratio show promise for in vivo imaging; however, such probes that can be selectively delivered into target sites and switch on afterglow luminescence remain limited. We optimize an organic electrochromic material and integrate it into near-infrared (NIR) photosensitizer (silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) and (poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene]) containing nanoparticles, developing an H2S-activatable NIR afterglow probe (F12+-ANP). F12+-ANP displays a fast reaction rate (1563 ± 141 M-1 s-1) and large afterglow turn-on ratio (~122-fold) toward H2S, enabling high-sensitivity and -specificity measurement of H2S concentration in bloods from healthy persons, hepatic or colorectal cancer patients. We further construct a hepatic-tumor-targeting and H2S-activatable afterglow probe (F12+-ANP-Gal) for noninvasive, real-time imaging of tiny subcutaneous HepG2 tumors (<3 mm in diameter) and orthotopic liver tumors in mice. Strikingly, F12+-ANP-Gal accurately delineates tumor margins in excised hepatic cancer specimens, which may facilitate intraoperative guidance of hepatic cancer surgery.

Engineering of Electrochromic Materials as Activatable Probes for Molecular Imaging and Photodynamic Therapy.

Electrochromic materials (EMs) are widely used color-switchable materials, but their applications as stimuli-responsive biomaterials to monitor and control biological processes remain unexplored. This study reports the engineering of an organic π-electron structure-based EM (dicationic 1,1,4,4-tetraarylbutadiene, 12+) as a unique hydrogen sulfide (H2S)-responsive chromophore amenable to build H2S-activatable fluorescent probes (12+-semiconducting polymer nanoparticles, 12+-SNPs) for in vivo H2S detection. We demonstrate that EM 12+, with a strong absorption (500-850 nm), efficiently quenches the fluorescence (580, 700, or 830 nm) of different fluorophores within 12+-SNPs, while the selective conversion into colorless diene 2 via H2S-mediated two-electron reduction significantly recovers fluorescence, allowing for non-invasive imaging of hepatic and tumor H2S in mice in real time. Strikingly, EM 12+ is further applied to design a near-infrared photosensitizer with tumor-targeting and H2S-activatable ability for effective photodynamic therapy (PDT) of H2S-related tumors in mice. This study demonstrates promise for applying EMs to build activatable probes for molecular imaging of H2S and selective PDT of tumors, which may lead to the development of new EMs capable of detecting and regulating essential biological processes in vivo.

Tumor-targeting CuS nanoparticles for multimodal imaging and guided photothermal therapy of lymph node metastasis.

Precise diagnosis of lymph node metastasis to guide lymphadenectomy is highly important for gastric cancer therapy in clinics. Though surgical dissection of regional metastatic lymph nodes remains the only way for gastric cancer therapy, the extended dissection may cause unavoidable postoperative risk of complications. It is still lack of effective method enabling the accurate removal of metastatic gastric cancer cells in lymph nodes with minimum injuries to normal tissue. Herein, we report a new fluorescent copper sulfide (CuS) nanoparticle (RGD-CuS-Cy5.5) enabling both non-invasive multimodality imaging and targeting photothermal therapy (PTT) of metastatic gastric cancer cells in lymph nodes. We demonstrate that RGD-CuS-Cy5.5 can easily drain into sentinel lymph nodes (SLN) after injection into primary tumors, and selectively enter into metastatic gastric MNK45 tumor cells via αvß3 integrin-mediated endocytosis. The resulting strong near-infrared (NIR) fluorescence and computed tomography (CT) contrast in metastatic SLN compared to normal SLN can precisely differentiate SLN metastasis of gastric cancers. Guided by the imaging, localized PTT with RGD-CuS-Cy5.5 is conducted upon irradiation with an 808 nm laser, resulting in complete removal of metastatic gastric tumor cells in SLN without obvious toxicity. Moreover, RGD-CuS-Cy5.5 can also allow for the rapid and non-invasive self-monitoring of PTT efficacy against metastatic SLNs in living mice. This study highlights the potential of using RGD-CuS-Cy5.5 for imaging-guided and targeting PTT of SLN metastasis in vivo, which may be applicable for the metastatic gastric cancer therapy in clinics. STATEMENT OF SIGNIFICANCE: RGD-CuS-Cy5.5 nanoparticles possess NIR fluorescence and CT signals for in vivo bimodality imaging of lymph node metastasis. Strong photothermal property under irradiation at 808 nm for efficient PTT. Easy drain into sentinel lymph nodes and selective enter metastatic gastric cancer cells via αvß3 integrin-mediated endocytosis. Rapid and non-invasive monitoring of therapeutic efficacy against lymph node metastasis.

Studies on the preparation and controlled release of redox/pH-responsive zwitterionic nanoparticles based on poly-L-glutamic acid and cystamine.

The enhancement of tumor intracellular drug uptake and resistance against nonspecific protein adsorption are essential for an injectable anticancer drug carrier. In the present study, a new type of redox/pH-responsive zwitterionic nanoparticles (NPs) was prepared using poly-L-glutamic acid and cystamine in aqueous solutions under mild conditions. The NPs showed surface charge convertible feature in response to pH change of the solutions. The NPs demonstrated excellent anti nonspecific protein adsorption. In vitro release profiles of the NPs, they showed redox/pH dual sensitivities in vitro release. The effective intracellular delivery behaviors were verified through investigation of cell viability, and confocal laser scanning microscopy observation of HeLa cells after incubation with the DOX-loaded NPs. The NPs were non-cytotoxic and would have potential applications as a drug delivery vehicle for enhancing intracellular uptake of anticancer drugs.

Zwitterionic pH/redox nanoparticles based on dextran as drug carriers for enhancing tumor intercellular uptake of doxorubicin.

Zwitterionic nanoparticles have excellent serum stability. In this study, pH/redox responsive polymer was synthesized through a modification of dextran using succinic acid, followed by crosslinking with cystamine. The polymer could self-assemble into stable nanoparticles (NPs) in aqueous solution. The NPs carried certain amount of free carboxyl and amino groups on the surface, which endowed the NPs excellent anti-protein adsorption ability. The surface charge was negative at pH7.4 and was converted to positive at pH5.0. It was revealed that the NPs showed little non-specific protein adsorption and had excellent serum stability, and the NPs could be internalized in Hela cells rapidly. This result was ascribed to the charge reversible feature of the NPs. Doxorubicin (DOX) was loaded in the NPs for release studies in vitro. The DOX-loaded NPs exhibited obvious pH and reduction sensitivities in response to the environment in tumor cells due to the introduction of carboxyl groups, amino groups and disulfide bonds in the NPs. The NPs were biocompatible, biodegradable, and could be potentially applied as anticancer drug carriers for enhancement of tumor intercellular uptake of doxorubicin.

Preparation of pH-sensitive zwitterionic nano micelles and drug controlled release for enhancing cellular uptake.

Zwitterionic copolymers have exhibited high resistance to nonspecific protein adsorption and have wide applications in drug delivery systems. Herein, a pH-responsive poly(Lysine-alt-N,N'-bis(acryloyl) diaminohexane) was synthesized through the Michael addition polymerization between N, N'-bis(acryloyl) diaminohexane and lysine. Subsequently, nano micelles (NMs) were formed by self-assembly of the copolymer in an aqueous solution. The NMs showed a slightly negative charge in blood environment, but a positively charged surface in extracellular pH of tumor. This feature could be used to enhance permeability and retention effect, and reinforce tumor cell uptake. Vitro release studies revealed that the release of DOX from the DOX-loaded NMs was evidently faster at pH 5.0 than at pH 7.4. MTT assays revealed that NMs were nontoxic. Thus, these smart NMs were feasible candidates and could be potentially used in cancer chemotherapy.

Surface Charge Convertible and Biodegradable Synthetic Zwitterionic Nanoparticles for Enhancing Cellular Drug Uptake.

To enhance drug cellular uptake, a biodegradable terpolymer is synthesized using taurine, N,N-Bis (acryloyl) cystamine, and dodecylamine as raw materials by Michael addition terpolymerization. The terpolymer is transformed to zwitterionic nanoparticles (NPs) through self-assembly. The surface charge of the NPs is convertible from negative at pH 7.4 to positive at pH 6.5, which endows the NPs' excellent nonfouling feature in bloodstream and effective uptake in tumor cells. The NPs display varied morphologies from solid micelles to polymersomes and nanorods depending on molar ratios of the structural units involved. The NPs can be biodegraded in l-glutathione (GSH) solution due to the split of disulfide bonds in main chains of the terpolymers. The NPs demonstrate good pH/reducing responsiveness in drug delivery and can be potentially used as anticancer drug vehicles for enhancement of cellular uptake of anticancer drug.