Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

Genetic Deletion of ß-Arrestin 2 From the Subfornical Organ and Other Periventricular Nuclei in the Brain Alters Fluid Homeostasis and Blood Pressure.

BACKGROUND: ANG (angiotensin II) elicits dipsogenic and pressor responses via activation of the canonical Gαq (G-protein component of the AT1R [angiotensin type 1 receptor])-mediated AT1R in the subfornical organ. Recently, we demonstrated that ARRB2 (ß-arrestin 2) global knockout mice exhibit a higher preference for salt and exacerbated pressor response to deoxycorticosterone acetate salt. However, whether ARRB2 within selective neuroanatomical nuclei alters physiological responses to ANG is unknown. Therefore, we hypothesized that ARRB2, specifically in the subfornical organ, counterbalances maladaptive dipsogenic and pressor responses to the canonical AT1R signaling. METHODS: Male and female Arrb2FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2ICV-Cre). Arrb2FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl. RESULTS: Arrb2ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2ICV-Cre mice exhibited elevated saline intake. CONCLUSIONS: Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT1R responses to both exogenous and endogenous ANG. Stimulation of the AT1R/ARRB axis in the brain may represent a novel strategy to treat hypertension.

Ionic Liquid Coating-Driven Nanoparticle Delivery to the Brain: Applications for NeuroHIV.

Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, the CNS acts as a latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate HIV, and given CNS infection, patients experience neurological deficits collectively referred to as "neuroHIV". Herein, the development of bioinspired ionic liquid-coated nanoparticles (IL-NPs) for in situ hitchhiking on red blood cells (RBCs) is reported, which enables 48% brain delivery of intracarotid arterial- infused cargo. Moreover, IL choline trans-2-hexenoate (CA2HA 1:2) demonstrates preferential accumulation in parenchymal microglia over endothelial cells post-delivery. This study further demonstrates successful loading of abacavir (ABC), an ART that is challenging to encapsulate, into IL-NPs, and verifies retention of antiviral efficacy in vitro. IL-NPs are not cytotoxic to primary human peripheral blood mononuclear cells (PBMCs) and the CA2HA 1:2 coating itself confers notable anti-viremic capacity. In addition, in vitro cell culture assays show markedly increased uptake of IL-NPs into neural cells compared to bare PLGA nanoparticles. This work debuts bioinspired ionic liquids as promising nanoparticle coatings to assist CNS biodistribution and has the potential to revolutionize the delivery of cargos (i.e., drugs, viral vectors) through compartmental barriers such as the blood-brain-barrier (BBB).

NIR-II emissive donor-acceptor-donor fluorophores for dual fluorescence bioimaging and photothermal therapy applications.

Fluorescence bioimaging with near-infrared II (NIR-II) emissive organic fluorophores has proven to be a viable noninvasive diagnostic technique. However, there is still the need for the development of fluorophores that possess increased stability as well as functionalities that impart stimuli responsiveness. Through strategic design, we can synthesize fluorophores that possess not only NIR-II optical profiles but also pH-sensitivity and the ability to generate heat upon irradiation. In this work, we employ a donor-acceptor-donor (D-A-D) design to synthesize a series of NIR-II fluorophores. Here we use thienothiadiazole (TTD) as the acceptor, 3-hexylthiophene (HexT) as the π-spacer and vary the alkyl amine donor units: N,N-dimethylaniline (DMA), phenylpiperidine (Pip), and phenylmorpholine (Morp). Spectroscopic analysis shows that all three derivatives exhibit emission in the NIR-II region with λemimax ranging from 1030 to 1075 nm. Upon irradiation, the fluorophores exhibited noticeable heat generation through non-radiative processes. The ability to generate heat indicates that these fluorophores will act as theranostic (combination therapeutic and diagnostic) agents in which simultaneous visualization and treatment can be performed. Additionally, biosensing capabilities were supported by changes in the absorbance properties while under acidic conditions as a result of protonation of the alkyl amine donor units. The fluorophores also show minimal toxicity in a human mammary cell line and with murine red blood cells. Overall, initial results indicate viable NIR-II materials for multiple biomedical applications.

Ionic liquid-coated lipid nanoparticles increase siRNA uptake into CNS targets.

Lipidoid nanoparticles (LNPs) have transformed the field of drug delivery and are clinically used for the delivery of nucleic acids to liver and muscle targets. Post-intravenous administration, LNPs are naturally directed to the liver due to the adsorption of plasma proteins like apolipoprotein E. In the present work, we have re-engineered LNPs with ionic liquids (ILs) to reduce plasma protein adsorption and potentially increase the accumulation of LNPs in hard-to-deliver central nervous system (CNS) targets such as brain endothelial cells (BECs) and neurons. We have developed two approaches to re-engineer LNPs using a choline trans-2-hexenoate IL: first, we have optimized an IL-coating process using the standard LNP formulation and in the second approach, we have incorporated ILs into the LNPs by replacing the PEG-lipid component in the standard formulation using ILs. IL-coated as well as IL-incorporated LNPs were colloidally stable with morphologies similar to the standard LNPs. IL-coated LNPs showed superior uptake into mouse BECs and neurons and demonstrated reduced mouse plasma protein adsorption compared to the standard LNPs. Overall, our results (1) demonstrate the feasibility of re-engineering the clinically approved LNP platform with highly tunable biomaterials like ILs for the delivery of therapeutics to CNS targets like BECs and neurons and (2) suggest that the surface properties of LNPs play a critical role in altering their affinity to and uptake into hard-to-deliver cell types.

Imidazolium-based zwitterionic liquid-modified PEG-PLGA nanoparticles as a potential intravenous drug delivery carrier.

Zwitterionic-based systems offer promise as next-generation drug delivery biomaterials capable of enhancing nanoparticle (NP) stimuli-responsiveness, biorecognition, and biocompatibility. Further, imidazole-functionalized amphiphilic zwitterions are able to readily bind to various biological macromolecules, enabling antifouling properties for enhanced drug delivery efficacy and bio-targeting. Herein, we describe structurally tuned zwitterionic imidazole-based ionic liquid (ZIL)-coated PEG-PLGA nanoparticles made with sonicated nanoprecipitation. Upon ZIL surface modification, the hydrodynamic radius increased by nearly 20 nm, and the surface charge significantly shifted closer to neutral. 1H NMR spectra suggests that the amount of ZIL on the nanoparticle surface is controlled by the structure of the ZIL and that the assembly occurs as a result of non-covalent interactions of ZIL-coated nanoparticle with the polymer surface. These nanoparticle-zwitterionic liquid (ZIL) constructs demonstrate selective affinity towards red blood cells in whole mouse blood and show relatively low human hemolysis at ∼5%. Additionally, we observe higher nanoparticle accumulation of ZIL-NPs compared with unmodified NP controls in human triple-negative breast cancer cells (MDA-MB-231). Furthermore, although the ZIL shows similar protein adsorption by SDS-PAGE, LC-MS/MS protein analysis data demonstrate a difference in the relative abundance and depletion of proteins in mouse and human serum. Hence, we show that ZIL-coated nanoparticles provide a new potential platform to enhance RBC-based drug delivery systems for cancer treatments.

Latent bloodstain detection using a selective turn-on NIR fluorescence dye responsive to serum albumin.

Bloodstain detection can provide crucial information and evidence at a crime scene; however, the ability to selectively detect bloodstains in a non-destructive manner with high sensitivity and low background is limited. This study reports a fluorescent dye (sulfonate indolizine squaraine, SO3SQ) for bloodstain visualization under near-infrared (NIR) irradiation. While the dye itself is minimally fluorescent in aqueous solution, it exhibits a "turn-on" mechanism upon binding with human serum albumin (HSA) as the fluorescence intensity increases over 160 times with strong absorption and emission at 693 nm and 758 nm, respectively. Bloodstains can be visualized on a surface even after being diluted 1000 times, and washed latent bloodstains can be detected with high sensitivity. Further, the turn-on fluorescent emission lasts for a minimum of seven days, allowing adequate time for detection. This study also indicates that the SO3SQ can sensitively detect bloodstain after the bloodstain aged for one week. Furthermore, the detection of latent blood fingerprint patterns from colorful backgrounds is demonstrated using this non-destructive method. The selective turn-on fluorescent dye with NIR excitation and emission is highly suitable in forensic science for bloodstain visualization.

Development of ionic liquid-coated PLGA nanoparticles for applications in intravenous drug delivery.

Polymeric nanoparticles (NPs) are a promising platform for medical applications in drug delivery. However, their use as drug carriers is limited by biological (e.g., immunological) barriers after intravenous administration. Ionic liquids (ILs), formed from bulky asymmetric cations and anions, have a wide variety of physical internal and external interfacing properties. When assembled on polymeric NPs as biomaterial coatings, these external-interfacing properties can be tuned to extend their circulation half-life when intravenously injected, as well as drive biodistribution to sites of interest for selective organ accumulation. In our work, we are particularly interested in optimizing IL coatings to enable red blood cell hitchhiking in whole blood. In this protocol, we describe the preparation and physicochemical and biological characterization of choline carboxylate IL-coated polymeric NPs. The procedure is divided into five stages: (1) synthesis and characterization of choline-based ILs (1 week); (2) bare poly(lactic-co-glycolic acid) (50:50, acid terminated) Resomer 504H (PLGA) NP assembly, modified from previously established protocols, with dye encapsulation (7 h); (3) modification of the bare particles with IL coating (3 h); (4) physicochemical characterization of both PLGA and IL-PLGA NPs by dynamic light scattering, 1H nuclear magnetic resonance spectroscopy, and transmission electron microscopy (1 week); (5) ex vivo evaluation of intravenous biocompatibility (including serum-protein resistance and hemolysis) and red blood cell hitchhiking in whole BALB/c mouse blood via fluorescence-activated cell sorting (1 week). With practice and technique refinement, this protocol is accessible to late-stage graduate students and early-stage postdoctoral scientists.

Selective Near-Infrared Blood Detection Driven by Ionic Liquid-Dye-Albumin Nanointeractions.

Due to its abundance in blood, a great deal of research has been undertaken to develop efficient biosensors for serum albumin and provide insight into the interactions that take place between these biosensing molecules and the protein. Near-infrared (NIR, >700 nm) organic dyes have been shown to be effective biosensors of serum albumin, but their effectiveness is diminished in whole blood. Herein, it is shown that an NIR sulfonate indolizine-donor-based squaraine dye, SO3SQ, can be strengthened as a biosensor of albumin through the addition of biocompatible ionic liquids (ILs). Specifically, the IL choline glycolate (1:1), at a concentration of 160 mM, results in the enhanced fluorescence emission ("switch-on") of the dye in the presence of blood. The origin of the fluorescence enhancement was investigated via methods, including DLS, ITC, and molecular dynamics. Further, fluorescence measurements were conducted to see the impact the dye-IL system had on the fluorescence of the tryptophan residue of human serum albumin (HSA), as well as to determine its apparent association constants in relation to albumin. Circular dichroism (CD) spectroscopy was used to provide evidence that the dye-IL system does not alter the secondary structures of albumin or DNA. Our results suggest that the enhanced fluorescence of the dye in the presence of IL and blood is due to diversification of binding sites in albumin, controlled by the interaction of the IL-dye-albumin complex.

Selective Blood Cell Hitchhiking in Whole Blood with Ionic Liquid-Coated PLGA Nanoparticles to Redirect Biodistribution After Intravenous Injection.

Less than 5% of intravenously-injected nanoparticles (NPs) reach destined sites in the body due to opsonization and immune-based clearance in vascular circulation. By hitchhiking in situ onto specific blood components post-injection, NPs can selectively target tissue sites for unprecedentedly high drug delivery rates. Choline carboxylate ionic liquids (ILs) are biocompatible liquid salts <100X composed of bulky asymmetric cations and anions. This class of ILs has been previously shown to significantly extend circulation time and redirect biodistribution in BALB/c mice post-IV injection via hitchhiking on red blood cell (RBC) membranes. Herein, we synthesized & screened 60 choline carboxylic acid-based ILs to coat PLGA NPs and present the impact of structurally engineering the coordinated anion identity to selectively interface and hitchhike lymphocytes, monocytes, granulocytes, platelets, and RBCs in whole mouse blood for in situ targeted drug delivery. Furthermore, we find this nanoparticle platform to be biocompatible (non-cytotoxic), translate to human whole blood by resisting serum uptake and maintaining modest hitchhiking, and also significantly extend circulation retention over 24 hours in BALB/c healthy adult mice after IV injection. Because of their altered circulation profiles, we additionally observe dramatically different organ accumulation profiles compared to bare PLGA NPs. This study establishes an initial breakthrough platform for a modular and transformative targeting technology to hitchhike onto blood components with high efficacy and safety in the bloodstream post-IV administration.

Substance Use and Mental Health Comorbidities and Receipt of Specialty Care Among Patients Enrolled in a Low-Barrier HIV Clinic.

Low-barrier care is one model of a differentiated service delivery approach for people with HIV (PWH) who are not engaged in conventionally-organized HIV care. Although psychiatric and substance use disorders are common among patients in low-barrier clinics, approaches to behavioral health service delivery within this context have not been well-described. We conducted a descriptive analysis using retrospective review of medical records to evaluate substance use and psychiatric comorbidities and receipt of behavioral health services among patients in the Max Clinic in Seattle, Washington. Among 227 patients enrolled from 2015 to mid-2020, most had a history of hazardous substance use (85%), a psychiatric diagnosis (69%) or unstable housing (69%) documented in the medical record. Less than half of patients referred for depression treatment (33%) or for opioid use disorder treatment (40%) completed even one specialty care visit. More effective approaches are needed to engage patients in behavioral health services within the context of low-barrier HIV care.

Lipid nanoparticle-mediated drug delivery to the brain.

Lipid nanoparticles (LNPs) have revolutionized the field of drug delivery through their applications in siRNA delivery to the liver (Onpattro) and their use in the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines. While LNPs have been extensively studied for the delivery of RNA drugs to muscle and liver targets, their potential to deliver drugs to challenging tissue targets such as the brain remains underexplored. Multiple brain disorders currently lack safe and effective therapies and therefore repurposing LNPs could potentially be a game changer for improving drug delivery to cellular targets both at and across the blood-brain barrier (BBB). In this review, we will discuss (1) the rationale and factors involved in optimizing LNPs for brain delivery, (2) ionic liquid-coated LNPs as a potential approach for increasing LNP accumulation in the brain tissue and (3) considerations, open questions and potential opportunities in the development of LNPs for delivery to the brain.

Topical Administration of an Apoptosis Inducer Mitigates Bleomycin-Induced Skin Fibrosis.

Pathological fibrosis is distinguished from physiological wound healing by persistent myofibroblast activation, suggesting that therapies that induce myofibroblast apoptosis selectively could prevent progression and potentially reverse the established fibrosis, such as for scleroderma (a heterogeneous autoimmune disease characterized by multiorgan fibrosis). Navitoclax (NAVI) is a BCL-2/BCL-xL inhibitor with antifibrotic properties and has been investigated as a potential therapeutic for fibrosis. NAVI makes myofibroblasts particularly vulnerable to apoptosis. However, despite NAVI's significant potency, clinical translation of BCL-2 inhibitors, NAVI in this case, is hindered due to the risk of thrombocytopenia. Therefore, in this work, we utilized a newly developed ionic liquid formulation of NAVI for direct topical application to the skin, thereby avoiding systemic circulation and off-target-mediated side effects. The ionic liquid composed of choline and octanoic acid (COA) at a 1:2 molar ionic ratio increases skin diffusion and transportation of NAVI and maintains their retention within the dermis for a prolonged duration. Topical administration of NAVI-mediated BCL-xL and BCL-2 inhibition results in the transition of myofibroblast to fibroblast and ameliorates pre-existing fibrosis, as demonstrated in a scleroderma mouse model. We have observed a significant reduction of α-SMA and collagen, which are known as fibrosis marker proteins, as a result of the inhibition of anti-apoptotic proteins BCL-2/BCL-xL. Overall, our findings show that COA-assisted topical delivery of NAVI upregulates apoptosis specific to myofibroblasts, with minimal presence of the drug in the systemic circulation, resulting in an accelerated therapeutic effect with no discernible drug-associated toxicity.

Ionic Liquid Coating-Driven Nanoparticle Delivery to the Brain: Applications for NeuroHIV.

Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, the CNS acts as a latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate HIV, and given CNS infection, patients experience an array of neurological deficits that are collectively referred to as 'neuroHIV'. Herein we report the development of bioinspired ionic liquid-coated nanoparticles (IL-NPs) for in situ hitchhiking on red blood cells (RBCs), which enabled 48% delivery of intravenously infused cargo to the brain. Moreover, the ionic liquid (IL) choline trans-2-hexenoate (CA2HA 1:2) demonstrated preferential accumulation in parenchymal microglia over endothelial cells post-delivery. We further demonstrate the successful loading of abacavir (ABC), an ART that is challenging to encapsulate, into the IL-coated NPs and verify the retention of antiviral efficacy in vitro. IL-NPs were not cytotoxic to primary human peripheral blood mononuclear cells (PBMCs) and the CA2HA 1:2 coating conferred notable anti-viremic capacity on its own. In addition, in vitro cell culture assays showed markedly increased uptake of IL-coated nanoparticles into neuronal cells compared to bare nanoparticles. This work debuts bioinspired ionic liquids as promising nanoparticle coatings to assist CNS biodistribution and has the potential to revolutionize the delivery of cargos (i.e., drugs, viral vectors) through compartmental barriers such as the blood-brain-barrier (BBB), illustrated in the graphical abstract below.

Good's Buffer Based Highly Biocompatible Ionic Liquid Modified PLGA Nanoparticles for the Selective Uptake in Cancer Cells.

Achieving safe and efficacious drug delivery is still an outstanding challenge. Herein we have synthesized 20 biocompatible Good's buffer-based ionic liquids (GBILs) with a range of attractive properties for drug delivery applications. The synthesized GBILs were used to coat the surface of poly(lactic-co-glycolic acid) (PLGA) by nanoprecipitation-sonication and characterized by dynamic light scattering (DLS) and proton nuclear magnetic resonance (1H NMR) spectroscopy. The GBIL-modified PLGA NPs were then tested for their interaction with bio-interfaces such as serum proteins (using SDS-PAGE and LCMS) and red blood cells (RBCs) isolated from human and BALB/c mouse blood. In this report, we show that surface modification of PLGA with certain GBILs led to modulation of preferential cellular uptake towards human triple-negative breast cancer cells (MDA-MB-231) compared to human normal healthy breast cells (MCF-10A). For example, cholinium N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonate (CBES) coated PLGA NPs were found to be selective for MDA-MB-231 cells (60.7 ± 0.7 %) as compared to MCF-10A cells (27.3 ± 0.7 %). In this way, GBIL-coatings have increased PLGA NP uptake in the cancer cells by 2-fold while decreasing the uptake towards normal healthy breast cells. Therefore, GBIL-modified nanoparticles could be a versatile platform for targeted drug delivery and gene therapy applications, as their surface properties can be tailored to interact with specific cell receptors and enhance cellular uptake. This formulation technique has shown promising results for targeting specific cells, which could be explored further for other cell types to achieve site-specific and efficient delivery of therapeutic agents.

Report: A Pox Presenting Without Pox.

ABSTRACT: A man with virally suppressed human immunodeficiency virus (HIV) presented with an erythematous, morbilliform rash without pustules in the setting of fever, fatigue, and myalgias after recent travel to Mexico and Puerto Rico. He was diagnosed with nonvariola orthopoxvirus (monkeypox) infection. This case report highlights an atypical presentation in the 2022 outbreak.

PHYTOCHROME-INTERACTING FACTOR 4/HEMERA-mediated thermosensory growth requires the Mediator subunit MED14.

While moderately elevated ambient temperatures do not trigger stress responses in plants, they do substantially stimulate the growth of specific organs through a process known as thermomorphogenesis. The basic helix-loop-helix transcription factor PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) plays a central role in regulating thermomorphogenetic hypocotyl elongation in various plant species, including Arabidopsis (Arabidopsis thaliana). Although it is well known that PIF4 and its co-activator HEMERA (HMR) promote plant thermosensory growth by activating genes involved in the biosynthesis and signaling of the phytohormone auxin, the detailed molecular mechanism of such transcriptional activation is not clear. In this report, we investigated the role of the Mediator complex in the PIF4/HMR-mediated thermoresponsive gene expression. Through the characterization of various mutants of the Mediator complex, a tail subunit named MED14 was identified as an essential factor for thermomorphogenetic hypocotyl growth. MED14 was required for the thermal induction of PIF4 target genes but had a marginal effect on the levels of PIF4 and HMR. Further transcriptomic analyses confirmed that the expression of numerous PIF4/HMR-dependent, auxin-related genes required MED14 at warm temperatures. Moreover, PIF4 and HMR physically interacted with MED14 and both were indispensable for the association of MED14 with the promoters of these thermoresponsive genes. While PIF4 did not regulate MED14 levels, HMR was required for the transcript abundance of MED14. Taken together, these results unveil an important thermomorphogenetic mechanism, in which PIF4 and HMR recruit the Mediator complex to activate auxin-related growth-promoting genes when plants sense moderate increases in ambient temperature.

ROS-Responsive Glycopolymeric Nanoparticles for Enhanced Drug Delivery to Macrophages.

Macrophages play a diverse, key role in many pathologies, including inflammatory diseases, cardiovascular diseases, and cancer. However, many therapeutic strategies targeting macrophages suffer from systemic off-target toxicity resulting in notoriously narrow therapeutic windows. To address this shortcoming, the development of poly(propylene sulfide)-b-poly(methacrylamidoglucopyranose) [PPS-b-PMAG] diblock copolymer-based nanoparticles (PMAG NPs) capable of targeting macrophages and releasing drug in the presence of reactive oxygen species (ROS) is reported. PMAG NPs have desirable physicochemical properties for systemic drug delivery, including slightly negative surface charge, ≈100 nm diameter, and hemo-compatibility. Additionally, due to the presence of PPS in the NP core, PMAG NPs release drug cargo preferentially in the presence of ROS. Importantly, PMAG NPs display high cytocompatibility and are taken up by macrophages in cell culture at a rate ≈18-fold higher than PEGMA NPs-NPs composed of PPS-b-poly(oligoethylene glycol methacrylate). Computational studies indicate that PMAG NPs likely bind with glucose transporters such as GLUT 1/3 on the macrophage cell surface to facilitate high levels of internalization. Collectively, this study introduces glycopolymeric NPs that are uniquely capable of both receptor-ligand targeting to macrophages and ROS-dependent drug release and that can be useful in many immunotherapeutic settings.