CMPK2 restricts Zika virus replication by inhibiting viral translation.

Flaviviruses continue to emerge as global health threats. There are currently no Food and Drug Administration (FDA) approved antiviral treatments for flaviviral infections. Therefore, there is a pressing need to identify host and viral factors that can be targeted for effective therapeutic intervention. Type I interferon (IFN-I) production in response to microbial products is one of the host's first line of defense against invading pathogens. Cytidine/uridine monophosphate kinase 2 (CMPK2) is a type I interferon-stimulated gene (ISG) that exerts antiviral effects. However, the molecular mechanism by which CMPK2 inhibits viral replication is unclear. Here, we report that CMPK2 expression restricts Zika virus (ZIKV) replication by specifically inhibiting viral translation and that IFN-I- induced CMPK2 contributes significantly to the overall antiviral response against ZIKV. We demonstrate that expression of CMPK2 results in a significant decrease in the replication of other pathogenic flaviviruses including dengue virus (DENV-2), Kunjin virus (KUNV) and yellow fever virus (YFV). Importantly, we determine that the N-terminal domain (NTD) of CMPK2, which lacks kinase activity, is sufficient to restrict viral translation. Thus, its kinase function is not required for CMPK2's antiviral activity. Furthermore, we identify seven conserved cysteine residues within the NTD as critical for CMPK2 antiviral activity. Thus, these residues may form an unknown functional site in the NTD of CMPK2 contributing to its antiviral function. Finally, we show that mitochondrial localization of CMPK2 is required for its antiviral effects. Given its broad antiviral activity against flaviviruses, CMPK2 is a promising potential pan-flavivirus inhibitor.

Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles.

Keratinocyte-derived carcinomas, including squamous cell carcinoma (SCC), comprise the most common malignancies. Surgical excision is the therapeutic standard but is not always clinically feasible, and currently available alternatives are limited to superficial tumors. To address the need for a nonsurgical treatment for nodular skin cancers like SCC, we developed a bioadhesive nanoparticle (BNP) drug delivery system composed of biodegradable polymer, poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), encapsulating camptothecin (CPT). Nanoparticles (NPs) of PLA-HPG are nonadhesive NPs (NNPs), which are stealthy in their native state, but we have previously shown that conversion of the vicinal diols of HPG to aldehydes conferred NPs the ability to form strong covalent bonds with amine-rich surfaces. Herein, we show that these BNPs have significantly enhanced binding to SCC tumor cell surfaces and matrix proteins, thereby significantly enhancing the therapeutic efficacy of intratumoral drug delivery. Tumor injection of BNP-CPT resulted in tumor retention of CPT at ∼50% at 10 d postinjection, while CPT was undetectable in NNP-CPT or free (intralipid) CPT-injected tumors at that time. BNP-CPT also significantly reduced tumor burden, with a portion (∼20%) of BNP-CPT-treated established tumors showing histologic cure. Larger, more fully established PDV SCC tumors treated with a combination of BNP-CPT and immunostimulating CpG oligodeoxynucleotides exhibited enhanced survival relative to controls, revealing the potential for BNP delivery to be used along with local tumor immunotherapy. Taken together, these results indicate that percutaneous delivery of a chemotherapeutic agent via BNPs, with or without adjuvant immunostimulation, represents a viable, nonsurgical alternative for treating cutaneous malignancy.

Targeted Drug Delivery to Stroke via Chemotactic Recruitment of Nanoparticles Coated with Membrane of Engineered Neural Stem Cells.

Cell membrane coating has recently emerged as a promising biomimetic approach to engineering nanoparticles (NPs) for targeted drug delivery. However, simple cell membrane coating may not meet the need for efficient drug delivery to the brain. Here, a novel molecular engineering strategy to modify the surface of NPs with a cell membrane coating for enhanced brain penetration is reported. By using poly(lactic-co-glycolic) acid NPs as a model, it is shown that delivery of NPs to the ischemic brain is enhanced through surface coating with the membrane of neural stem cells (NSCs), and the delivery efficiency can be further increased using membrane isolated from NSCs engineered for overexpression of CXCR4. It is found that this enhancement is mediated by the chemotactic interaction of CXCR4 with SDF-1, which is enriched in the ischemic microenvironment. It is demonstrated that the resulting CXCR4-overexpressing membrane-coated NPs, termed CMNPs, significantly augment the efficacy of glyburide, an anti-edema agent, for stroke treatment. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve management of human patients with stroke.

Understanding the Solution and Solid-State Structures of Pd and Pt PSiP Pincer-Supported Hydrides.

The PSiP pincer-supported complex ((Cy)PSiP)PdH [(Cy)PSiP = Si(Me)(2-PCy2-C6H4)2] has been implicated as a crucial intermediate in carboxylation of both allenes and boranes. At this stage, however, there is uncertainty regarding the exact structure of ((Cy)PSiP)PdH, especially in solution. Previously, both a Pd(II) structure with a terminal Pd hydride and a Pd(0) structure featuring an η(2)-silane have been proposed. In this contribution, a range of techniques were used to establish that ((Cy)PSiP)PdH and the related Pt species, ((Cy)PSiP)PtH, are true M(II) hydrides in both the solid state and solution. The single-crystal X-ray structures of ((Cy)PSiP)MH (M = Pd and Pt) and the related species ((iPr)PSiP)PdH [(iPr)PSiP = Si(Me)(2-P(i)Pr2-C6H4)2] are in agreement with the presence of a terminal metal hydride, and the exact geometry of ((Cy)PSiP)PtH was confirmed using neutron diffraction. The (1)H and (29)Si{(1)H}NMR chemical shifts of ((Cy)PSiP)MH (M = Pd and Pt) are consistent with a structure containing a terminal hydride, especially when compared to the chemical shifts of related pincer-supported complexes. In fact, in this work, two general trends relating to the (1)H NMR chemical shifts of group 10 pincer-supported terminal hydrides were elucidated: (i) the hydride shift moves downfield from Ni to Pd to Pt and (ii) the hydride shift moves downfield with more trans-influencing pincer central donors. DFT calculations indicate that structures containing a M(II) hydride are lower in energy than the corresponding η(2)-silane isomers. Furthermore, the calculated NMR chemical shifts of the M(II) hydrides using a relativistic four-component methodology incorporating all significant scalar and spin-orbit corrections are consistent with those observed experimentally. Finally, in situ X-ray absorption spectroscopy (XAS) was used to provide further support that ((Cy)PSiP)MH exist as M(II) hydrides in solution.

An unusual example of hypervalent silicon: a five-coordinate silyl group bridging two palladium or nickel centers through a nonsymmetrical four-center two-electron bond.

Pd and Ni dimers supported by PSiP ligands in which two hypervalent five-coordinate Si atoms bridge the two metal centers are reported. Crystallographic characterization revealed a rare square-pyramidal geometry at Si and an unusual asymmetric M2 Si2 core (M=Pd or Ni). DFT calculations showed that the unusual structure of the core is also found in a model in which the phosphine and Si centers are not part of a pincer group, thus indicating that the observed geometry is not imposed by the PSiP ligand. NBO analysis showed that an asymmetric four-center two-electron (4c-2e) bond stabilizes the hypervalent Si atoms in the M2 Si2 core.

Nanoscale Surface Topography of Polyethylene Glycol-Coated Nanoparticles Composed of Bottlebrush Block Copolymers Prolongs Systemic Circulation and Enhances Tumor Uptake.

Improving the performance of nanocarriers remains a major challenge in the clinical translation of nanomedicine. Efforts to optimize nanoparticle formulations typically rely on tuning the surface density and thickness of stealthy polymer coatings, such as poly(ethylene glycol) (PEG). Here, we show that modulating the surface topography of PEGylated nanoparticles using bottlebrush block copolymers (BBCPs) significantly enhances circulation and tumor accumulation, providing an alternative strategy to improve nanoparticle coatings. Specifically, nanoparticles with rough surface topography achieve high tumor cell uptake in vivo due to superior tumor extravasation and distribution compared to conventional smooth-surfaced nanoparticles based on linear block copolymers. Furthermore, surface topography profoundly impacts the interaction with serum proteins, resulting in the adsorption of fundamentally different proteins onto the surface of rough-surfaced nanoparticles formed from BBCPs. We envision that controlling the nanoparticle surface topography of PEGylated nanoparticles will enable the design of improved nanocarriers in various biomedical applications.

Exploiting Metabolic Defects in Glioma with Nanoparticle Encapsulated NAMPT Inhibitors.

The treatment of primary central nervous system (CNS) tumors is challenging due to the blood-brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas (IDH-WT and mutant, WHO grades II-IV; with grade IV tumors referred to as glioblastomas; GBMs). These mutations drive epigenetic changes, leading to promoter methylation at the NAPRT gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT-silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, NAMPT, rationalizing a treatment for these malignancies. Multiple systemically-administered NAMPTis have been developed and tested in clinical trials, but dose-limiting toxicities-including bone marrow suppression and retinal toxicity-have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle-encapsulated (NP) NAMPT inhibitors (NAMPTis) administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.

Intensive harmonized synapses with amorphous Cu2O-based memristors using ultrafine Cu nanoparticle sublayers formed via atomically controlled electrochemical pulse deposition.

Resistive random-access memory (RRAM) devices have significant advantages for neuromorphic computing but have fatal problems of uncontrollability and abrupt resistive switching behaviors degrading their synaptic performance. In this paper, we propose the electrochemical design of an active Cu2O layer containing a strategic sublayer of ultrafine Cu nanoparticles (U-Cu NPs) to form uniformly dispersed conducting filaments, which can effectively improve the reliability for analog switching of RRAM-based neuromorphic computing. The electrochemical pulse deposited (EPD) U-Cu NPs are linked to the bottom electrode through a semi-conductive path within the bottom Cu2O layer, since the EPD is preferentially carried out on the conductive sites. All Cu2O films with U-Cu NPs are developed in situ in the single electrolyte bath without any pause. The proposed U-Cu NPs can concentrate the external electric field and can generate conductive filament paths for analog resistive switching. The applied electric field was uniformly spread to U-Cu NPs at the center of the active layer and displays resistive switching behavior via multiple conductive filaments. This shows a strong harmony between the resistance-switching characteristics and the analog operation of the active layer. This RRAM device shows outstanding gradual analog switching, great linearity, dynamic range, endurance, precision, speed, and retention characteristics simultaneously and adequately for neuromorphic computing by realizing multiple weak filament-type operation.

Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy.

Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination.

An inhalable platform for messenger RNA (mRNA) therapeutics would enable minimally invasive and lung-targeted delivery for a host of pulmonary diseases. Development of lung-targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here, we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) (PACE) polyplexes for mRNA delivery using end-group modifications and polyethylene glycol. These polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for severe acute respiratory syndrome coronavirus 2 and found that intranasal vaccination with spike protein-encoding mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected susceptible mice from lethal viral challenge. Together, these results demonstrate the translational potential of PACE polyplexes for therapeutic delivery of mRNA to the lungs.

Retraction: Progressive p-channel vertical transistors fabricated using electrodeposited copper oxide designed with grain boundary tunability.

Retraction of 'Progressive p-channel vertical transistors fabricated using electrodeposited copper oxide designed with grain boundary tunability' by Sung Hyeon Jung et al., Mater. Horiz., 2022, 9, 1010-1022, https://doi.org/10.1039/D1MH01568K.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

Design of Functionally Stacked Channels of Oxide Thin-Film Transistors to Mimic Precise Ultralow-Light-Irradiated Synaptic Weight Modulation.

To utilize continuous ultralow intensity signals from oxide synaptic transistors as artificial synapses that mimic human visual perception, we propose strategic oxide channels that optimally utilize their advantageous functions by stacking two oxide semiconductors with different conductivities. The bottom amorphous indium-gallium-zinc oxide (a-IGZO) layer with a relatively low conductivity was designed for an extremely low initial postsynaptic current (PSCi) by achieving full depletion at a low negative gate voltage, and the stacked top amorphous indium-zinc oxide (a-IZO) layer improved the amplitude of the synaptic current and memory retention owing to the enhancement in the persistent photoconductivity characteristics. We demonstrated an excellent photonic synapse thin-film transistor (TFT) with a precise synaptic weight change even in the range of ultralow light intensity by adapting this stacking IGZO/IZO channel. The proposed device exhibited distinct ∆PSC values of 3.1 and 18.1 nA under ultralow ultraviolet light (350 nm, 50 ms) of 1.6 and 8.0 µW/cm2. In addition, while the lowest light input exhibited short-term plasticity characteristics similar to the "volatile-like" behavior of the human brain with a current recovery close to the initial value, the increase in light intensity caused long-term plasticity characteristics, thus achieving synaptic memory transition in the IGZO/IZO TFTs.

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination.

An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge. One-sentence summary: Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.

Direct targeting of amplified gene loci for proapoptotic anticancer therapy.

Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.

Progressive p-channel vertical transistors fabricated using electrodeposited copper oxide designed with grain boundary tunability.

A strategically designed electrodeposition method is proposed for the coating of p-type copper(i) oxide (Cu2O) channels for oxide thin film transistors. To date, conventional p-type oxide semiconductors have revealed a poor mobility and stability and this has obstructed the development of all oxide based logic devices. Furthermore, previous studies on p-type oxide transistors have been limited by the use of a typical planar type configuration. Our Cu2O electrodeposition method designed by incorporating Sb element promotes vertical alignment of the grain boundaries (GBs) and it perfectly coincides with the charge transport direction from the source to the drain in the vertical field effect transistors. These vertically aligned GBs are bundle type GBs and are likely to be ideal for vertical transistors with supreme electrical performances owing to the structurally suppressed grain boundary charge scattering. This alignment of the GBs in the electrodeposited Sb doped Cu2O (Sb:Cu2O) also demonstrates a superior vertical taper profile with conventional wet chemical etching owing to the extremely preferential etching rate along the GBs. Surprisingly, the sidewall formation, with a smooth and steep morphology causes the formation of abrupt and non-defective gate insulator/channel interfaces for superior spacer-free vertical transistors. Consequently, the Cu2O vertical field effect transistors exhibit extraordinary transistor performances of Vth = 0.4 V, µFE = 8 cm2 V-1 s-1, subthreshold swing = 0.24 V dec-1, on/off current ratio = 2 × 108 and qualified electrical and long-term stability characteristics under various environments. To the best of our knowledge, this is the first reported study on an electrodeposited method to design troublesome p-type oxide Cu2O as novel vertical transistors. Finally, power efficient logic inverter circuits with unprecedented performances, such as good noise margins, remarkable gain values of 15.6 (2 VDD) and 62.7 (5 VDD), and high frequency operation up to 10 kHz, are demonstrated using these p-type Cu2O transistors by interconnecting n-type IGZO transistors.

Polyglycerol and Poly(ethylene glycol) exhibit different effects on pharmacokinetics and antibody generation when grafted to nanoparticle surfaces.

Poly(ethylene glycol) (PEG) is widely employed for passivating nanoparticle (NP) surfaces to prolong blood circulation and enhance localization of NPs to target tissue. However, the immune response of PEGylated NPs-including anti-PEG antibody generation, accelerated blood clearance (ABC), and loss of delivery efficacy-is of some concern, especially for treatments that require repeat administrations. Although polyglycerol (PG), which has the same ethylene oxide backbone as PEG, has received attention as an alternative to PEG for NP coatings, the pharmacokinetic and immunogenic impact of PG has not been studied systematically. Here, linear PG, hyperbranched PG (hPG), and PEG-coated polylactide (PLA) NPs with varying surface densities were studied in parallel to determine the pharmacokinetics and immunogenicity of PG and hPG grafting, in comparison with PEG. We found that linear PG imparted the NPs a stealth property comparable to PEG, while hPG-grafted NPs needed a higher surface density to achieve the same pharmacokinetic impact. While linear PG-grafted NPs induced anti-PEG antibody production in mice, they exhibited minimal accelerated blood clearance (ABC) effects due to the poor interaction with anti-PEG immunoglobulin M (IgM). Further, we observed no anti-polymer IgM responses or ABC effects for hPG-grafted NPs.

Surface Topography of Polyethylene Glycol Shell Nanoparticles Formed from Bottlebrush Block Copolymers Controls Interactions with Proteins and Cells.

Although poly(ethylene glycol) (PEG) is commonly used in nanoparticle design, the impact of surface topography on nanoparticle performance in biomedical applications has received little attention, despite showing significant promise in the study of inorganic nanoparticles. Control of the surface topography of polymeric nanoparticles is a formidable challenge due to the limited conformational control of linear polymers that form the nanoparticle surface. In this work, we establish a straightforward method to precisely tailor the surface topography of PEGylated polymeric nanoparticles based on tuning the architecture of shape-persistent amphiphilic bottlebrush block copolymer (BBCP) building blocks. We demonstrate that nanoparticle formation and surface topography can be controlled by systematically changing the structural parameters of BBCP architecture. Furthermore, we reveal that the surface topography of PEGylated nanoparticles significantly affects their performance. In particular, the adsorption of a model protein and the uptake into HeLa cells were closely correlated to surface roughness and BBCP terminal PEG block brush width. Overall, our work elucidates the importance of surface topography in nanoparticle research as well as provides an approach to improve the performance of PEGylated nanoparticles.

Optimal n-Type Al-Doped ZnO Overlayers for Charge Transport Enhancement in p-Type Cu2O Photocathodes.

An effective strategy for improving the charge transport efficiency of p-type Cu2O photocathodes is the use of counter n-type semiconductors with a proper band alignment, preferably using Al-doped ZnO (AZO). Atomic layer deposition (ALD)-prepared AZO films show an increase in the built-in potential at the Cu2O/AZO interface as well as an excellent conformal coating with a thin thickness on irregular Cu2O. Considering the thin thickness of the AZO overlayers, it is expected that the composition of the Al and the layer stacking sequence in the ALD process will significantly influence the charge transport behavior and the photoelectrochemical (PEC) performance. We designed various stacking orders of AZO overlayers where the stacking layers consisted of Al2O3 (or Al) and ZnO using the atomically controlled ALD process. Al doping in ZnO results in a wide bandgap and does not degrade the absorption efficiency of Cu2O. The best PEC performance was obtained for the sample with an AZO overlayer containing conductive Al layers in the bottom and top regions. The Cu2O/AZO/TiO2/Pt photoelectrode with this overlayer exhibits an open circuit potential of 0.63 V and maintains a high cathodic photocurrent value of approximately -3.2 mA cm-2 at 0 VRHE for over 100 min.

Optimizing biodegradable nanoparticle size for tissue-specific delivery.

Nanoparticles (NPs) are promising vehicles for drug delivery because of their potential to target specific tissues [1]. Although it is known that NP size plays a critical role in determining their biological activity, there are few quantitative studies of the role of NP size in determining biodistribution after systemic administration. Here, we engineered fluorescent, biodegradable poly(lactic-co-glycolic acid) (PLGA) NPs in a range of sizes (120-440nm) utilizing a microfluidic platform and used these NPs to determine the effect of diameter on bulk tissue and cellular distribution after systemic administration. We demonstrate that small NPs (∼120nm) exhibit enhanced uptake in bulk lung and bone marrow, while larger NPs are sequestered in the liver and spleen. We also show that small NPs (∼120nm) access specific alveolar cell populations and hematopoietic stem and progenitor cells more readily than larger NPs. Our results suggest that size of PLGA NPs can be used to tune delivery to certain tissues and cell populations in vivo.