Look-alike, sound-alike (LASA) drugs in India.

Poor drug regulation in India is not a recent problem. The Indian drug market is full of look-alike, sound-alike (LASA) drugs which have not yet caught the attention of the media or the medical community. This viewpoint highlights the problem of LASA drugs and poor prescription practices and proposes solutions for involving all stakeholders in this unaddressed issue which is a huge public health problem in India.

Nanoparticle-mediated co-delivery of inflammasome inhibitors provides protection against sepsis.

The NLRP3 inflammasome, a multiprotein complex responsible for triggering the release of pro-inflammatory cytokines, plays a crucial role in inducing the inflammatory response associated with sepsis. While small molecule inhibitors of the NLRP3 inflammasome have been investigated for sepsis management, delivering NLRP3 inhibitors has been accompanied by several challenges, primarily related to the drug formulation, delivery route, stability, and toxicity. Many existing inflammasome inhibitors either show higher liver toxicity or require a high dosage to efficiently impede the inflammasome complex assembly. Moreover, the potential synergistic effects of combining multiple inflammasome inhibitors in sepsis therapy remain largely unexplored. Therefore, a rational approach is essential for presenting the potential administration of NLRP3 small molecule inhibitors to inhibit NLRP3 inflammasome activation effectively. In this context, we present a lipid nanoparticle-based dual-drug delivery system loaded with MCC 950 and disulfiram, demonstrating markedly higher efficiency compared to an equivalent amount of free-drug combinations and individual drug nanoparticles in vitro. This combination therapy substantially improved the in vivo survival rate of mice for LPS-induced septic peritonitis. Additionally, the synergistic approach illustrated a significant reduction in the expression of active caspase-1 as well as IL-1ß inhibition integral components in the NLRP3 pathway. This study underscores the importance of integrating combination therapies facilitated by nanoparticle delivery to address the limitations of small molecule inflammasome inhibitors.

Highly Ordered Eutectic Mesostructures via Template-Directed Solidification within Thermally Engineered Templates.

Template-directed self-assembly of solidifying eutectics results in emergence of unique microstructures due to diffusion constraints and thermal gradients imposed by the template. Here, the importance of selecting the template material based on its conductivity to control heat transfer between the template and the solidifying eutectic, and thus the thermal gradients near the solidification front, is demonstrated. Simulations elucidate the relationship between the thermal properties of the eutectic and template and the resultant microstructure. The overarching finding is that templates with low thermal conductivities are generally advantageous for forming highly organized microstructures. When electrochemically porosified silicon pillars (thermal conductivity < 0.3 Wm-1K-1) are used as the template into which an AgCl-KCl eutectic is solidified, 99% of the unit cells in the solidified structure exhibit the same pattern. In contrast, when higher thermal conductivity crystalline silicon pillars (≈100 Wm-1K-1) are utilized, the expected pattern is only present in 50% of the unit cells. The thermally engineered template results in mesostructures with tunable optical properties and reflectances nearly identical to the simulated reflectances of perfect structures, indicating highly ordered patterns are formed over large areas. This work highlights the importance of controlling heat flows in template-directed self-assembly of eutectics.

Flow-Induced Shear Stress Primes NLRP3 Inflammasome Activation in Macrophages via Piezo1.

The NLRP3 inflammasome is a crucial component of the innate immune system, playing a pivotal role in initiating and regulating the body's inflammatory response to various pathogens and cellular damage. Environmental stimuli, such as temperature, pH level, and nutrient availability, can influence the behavior and functions of innate immune cells, including immune cell activity, proliferation, and cytokine production. However, there is limited understanding regarding how mechanical forces, like shear stress, govern the intrinsic inflammatory reaction, particularly the activation of the NLRP3 inflammasome, and how shear stress impacts NLRP3 inflammasome activation through its capacity to induce alterations in gene expression and cytokine secretion. Here, we investigated how shear stress can act as a priming signal in NLRP3 inflammasome activation by exposing immortalized bone marrow-derived macrophages (iBMDMs) to numerous physiologically relevant magnitudes of shear stress before chemically inducing inflammasome activation. We demonstrated that shear stress of large magnitudes was able to prime iBMDMs more effectively for inflammasome activation compared to lower shear stress magnitudes, as quantified by the percentage of cells where ASC-CFP specks formed and IL-1ß secretion, the hallmarks of inflammasome activation. Testing this in NLRP3 and caspase-1 knockout iBMDMs showed that the NLRP3 inflammasome was primarily primed for activation due to shear stress exposure. Quantitative polymerase chain reaction (qPCR) and a small-molecule inhibitor study mechanistically determined that shear stress regulates the NLRP3 inflammasome by upregulating Piezo1, IKKß, and NLRP3. These findings offer insights into the mechanistic relationship among physiological shear stresses, inflammasome activation, and their impact on the progression of inflammatory diseases and their interconnected pathogenesis.

Caspase-1 Responsive Nanoreporter for In Vivo Monitoring of Inflammasome Immunotherapy.

Inflammasomes are multimeric protein signaling complexes that are assembled in innate immune cells in response to a multitude of pathogen and damage-associated signals. They are essential for generating robust inflammatory responses to prevent pathogenic insults. However, inflammasome dysregulation can induce cascading immune responses, resulting in systemic toxicities and inflammatory disease. In this sense, there is a strong need to develop potent inflammasome inhibiting therapies as well as technologies to monitor their efficacy, yet current systems lack the ability to effectively image inflammasome activation and track therapy response early. To overcome these limitations, we report a novel nanoparticle system delivering both a caspase-1 cleavable inflammasome detecting probe and the NLRP3 inhibitor drug MCC-950, providing dual capabilities of monitoring and regulation of inflammasome activation in a biocompatible, tissue penetrating, and sustained release liposomal formulation. We observed this liposomal nanoreporter's ability to reduce and detect inflammasome activation both in vitro in immortalized bone marrow-derived macrophages and in vivo in a DSS-induced ulcerative colitis mouse model. Our results exhibited the nanoreporter's ability to penetrate inflammatory tissues and detect inflammasome activation early and in real-time for multiple days while alleviating inflammation in the groups coencapsulating imaging reporter and inflammasome inhibitor. Overall, the developed liposomal nanoreporter platform enables spatiotemporal delivery of imaging probe and inhibitor, captures early and sustained inflammasome detection, and induces inflammasome amelioration, thus establishing a novel tool for the real-time monitoring and treatment of inflammasome-mediated disease with high potential for clinical application.

Intracellular Salmonella delivery of an exogenous immunization antigen refocuses CD8 T cells against cancer cells, eliminates pancreatic tumors and forms antitumor immunity.

Introduction: Immunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice. Methods: To test this hypothesis, we administered intracellular delivering (ID) Salmonella that deliver ovalbumin as a model antigen into tumor-bearing, ovalbumin-vaccinated mice. ID Salmonella delivers antigens by autonomously lysing in cells after the induction of cell invasion. Results: We showed that the delivered ovalbumin disperses throughout the cytoplasm of cells in culture and in tumors. This delivery into the cytoplasm is essential for antigen cross-presentation. We showed that co-culture of ovalbumin-recipient cancer cells with ovalbumin-specific CD8 T cells triggered a cytotoxic T cell response. After the adoptive transfer of OT-I CD8 T cells, intracellular delivery of ovalbumin reduced tumor growth and eliminated tumors. This effect was dependent on the presence of the ovalbumin-specific T cells. Following vaccination with the exogenous antigen in mice, intracellular delivery of the antigen cleared 43% of established KPC pancreatic tumors, increased survival, and prevented tumor re-implantation. Discussion: This response in the immunosuppressive KPC model demonstrates the potential to treat tumors that do not respond to checkpoint inhibitors, and the response to re-challenge indicates that new immunity was established against intrinsic tumor antigens. In the clinic, ID Salmonella could be used to deliver a protein antigen from a childhood immunization to refocus pre-existing T cell immunity against tumors. As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients.

Protein Corona Formation on Lipid Nanoparticles Negatively Affects the NLRP3 Inflammasome Activation.

The interaction between lipid nanoparticles (LNPs) and serum proteins, giving rise to a unique identification in the form of the protein corona, has been shown to be associated with novel recognition by cell receptors. The presence of the corona enveloping the nanoparticle strongly affects the interplay with immune cells. The immune responses mediated by protein corona can affect nanoparticle toxicity and targeting capabilities. But the intracellular signaling of LNPs after corona formation resulting in the change of nanoparticles' ability to provoke immune responses remains unclear. Therefore, a more systematic and delineated approach must be considered to present the correlation between corona complexes and the shift in nanoparticle immunogenicity. Here, we studied and reported the inhibiting effect of the absorbed proteins on the LNPs on the NLRP3 inflammasome activation, a key intracellular protein complex that modulates several inflammatory responses. Ionizable lipid as a component of LNP was observed to play an important role in modulating the activation of NLRP3 inflammasome in serum-free conditions. However, in the presence of serum proteins, the corona layer on LNPs caused a significant reduction in the inflammasome activation. Reduction in the lysosomal rupture after treatment with corona-LNPs significantly reduced inflammasome activation. Furthermore, a strong reduction of cellular uptake in macrophages after the corona formation was observed. On inspecting the uptake mechanisms in macrophages using transport inhibitors, lipid formulation was found to play a critical role in determining the endocytic pathways for the LNPs in macrophages. This study highlights the need to critically analyze the protein interactions with nanomaterials and their concomitant adaptability with immune cells to evaluate nano-bio surfaces and successfully design nanomaterials for biological applications.

Activatable Nanoreporters for Real-Time Tracking of Macrophage Phenotypic States Associated with Disease Progression.

Diagnosis of inflammatory diseases is characterized by identifying symptoms, biomarkers, and imaging. However, conventional techniques lack the sensitivities and specificities to detect disease early. Here, it is demonstrated that the detection of macrophage phenotypes, from inflammatory M1 to alternatively activated M2 macrophages, corresponding to the disease state can be used to predict the prognosis of various diseases. Activatable nanoreporters that can longitudinally detect the presence of the enzyme Arginase 1, a hallmark of M2 macrophages, and nitric oxide, a hallmark of M1 macrophages are engineered, in real-time. Specifically, an M2 nanoreporter enables the early imaging of the progression of breast cancer as predicted by selectively detecting M2 macrophages in tumors. The M1 nanoreporter enables real-time imaging of the subcutaneous inflammatory response that rises from a local lipopolysccharide (LPS) administration. Finally, the M1-M2 dual nanoreporter is evaluated in a muscle injury model, where an initial inflammatory response is monitored by imaging M1 macrophages at the site of inflammation, followed by a resolution phase monitored by the imaging of infiltrated M2 macrophages involved in matrix regeneration and wound healing. It is anticipated that this set of macrophage nanoreporters may be utilized for early diagnosis and longitudinal monitoring of inflammatory responses in various disease models.

Nanoreporter for Real-Time Monitoring of Inflammasome Activity and Targeted Therapy.

Inflammasome activation is associated with a myriad of inflammatory diseases. However, existing methods provides a limited understanding of spatiotemporal kinetics of inflammasome activation, with restricted scope for early detection of associated treatment efficacy. This limitation offers an opportunity for the development of biocompatible in-vivo inflammasome monitoring tools with translational prospects. To achieve this, they report developing a pair of lipid-based nanoparticle systems, a reporter nanoparticle consisting of a caspase-1 activatable probe alone, and a theranostic nanoparticle combining the probe with an inflammasome-inhibiting drug. This biocompatible platform enhances the probe's residence time in circulation by preventing its opsonization and allowing its sustained release over time. Their results demonstrate the specificity of reporter nanoparticles towards caspase-1 activity and provides early-on monitoring of inflammasome activation both in-vitro as well as in-vivo. Additionally, the delivery of disulfiram, an inflammasome-inhibiting drug, along with reporter probe using theranostic nanoparticles enables real-time tracking of treatment efficacy in the gouty-arthritis inflammatory model. In summary, they report an unparalleled pair of the inflammasome-associated reporter and theranostic platforms suited not only for diagnostic applications but can also detect inflammasome-targeted treatment efficiency in real-time. These findings establish two novel, sensitive nanotools for non-invasive evaluation of inflammasome-targeted immunotherapy.

Nanotheranostic Strategies for Cancer Immunotherapy.

Despite advancements in cancer immunotherapy, heterogeneity in tumor response impose barriers to successful treatments and accurate prognosis. Effective therapy and early outcome detection are critical as toxicity profiles following immunotherapies can severely affect patients' quality of life. Existing imaging techniques, including positron emission tomography, computed tomography, magnetic resonance imaging, or multiplexed imaging, are often used in clinics yet suffer from limitations in the early assessment of immune response. Conventional strategies to validate immune response mainly rely on the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified iRECIST for immuno-oncology drug trials. However, accurate monitoring of immunotherapy efficacy is challenging since the response does not always follow conventional RECIST criteria due to delayed and variable kinetics in immunotherapy responses. Engineered nanomaterials for immunotherapy applications have significantly contributed to overcoming these challenges by improving drug delivery and dynamic imaging techniques. This review summarizes challenges in recent immune-modulation approaches and traditional imaging tools, followed by emerging developments in three-in-one nanoimmunotheranostic systems co-opting nanotechnology, immunotherapy, and imaging. In addition, a comprehensive overview of imaging modalities in recent cancer immunotherapy research and a brief outlook on how nanotheranostic platforms can potentially advance to clinical translations for the field of immuno-oncology is presented.

mRNA-carrying lipid nanoparticles that induce lysosomal rupture activate NLRP3 inflammasome and reduce mRNA transfection efficiency.

In the last several years, countless developments have been made to engineer more efficient and potent mRNA lipid nanoparticle vaccines, culminating in the rapid development of effective mRNA vaccines against COVID-19. However, despite these advancements and materials approaches, there is still a lack of understanding of the resultant immunogenicity of mRNA lipid nanoparticles. Therefore, a more mechanistic, design-driven approach needs to be taken to determine which biophysical characteristics, especially related to changes in lipid compositions, drive nanoparticle immunogenicity. Here, we synthesized a panel of six mRNA lipid nanoparticle formulations, varying the concentrations of different lipid components and systematically studied their effect on NLRP3 inflammasome activation; a key intracellular protein complex that controls various inflammatory responses. Initial experiments aimed to determine differences in nanoparticle activation of NLRP3 inflammasomes by IL-1ß ELISA, which unveiled that nanoparticles with high concentrations of ionizable lipid DLin-MC3-DMA in tandem with high cationic lipid DPTAP and low cholesterol concentration induced the greatest activation of the NLRP3 inflammasome. These results were further corroborated by the measurement of ASC specks indicative of NLRP3 complex assembly, as well as cleaved gasdermin-D and caspase-1 expression indicating complex activation. We also uncovered these activation profiles to be mechanistically correlated primarily with lysosomal rupturing caused by the delayed membrane disruption capabilities of ionizable lipids until the lysosomal stage, as well as by mitochondrial reactive oxygen species (ROS) production and calcium influx for some of the particles. Therefore, we report that the specific, combined effects of each lipid type, most notably ionizable, cationic lipids, and cholesterol, is a crucial mRNA lipid nanoparticle characteristic that varies the endo/lysosomal rupture capabilities of the formulation and activate NLRP3 inflammasomes in a lysosomal rupture dependent manner. These results provide a more concrete understanding of mRNA lipid Nanoparticle-Associated Molecular Patterns for the activation of molecular-level immune responses and provide new lipid composition design considerations for future mRNA-delivery approaches.

Hierarchical, Self-Assembled Metasurfaces via Exposure-Controlled Reflow of Block Copolymer-Derived Nanopatterns.

Nanopatterning for the fabrication of optical metasurfaces entails a need for high-resolution approaches like electron beam lithography that cannot be readily scaled beyond prototyping demonstrations. Block copolymer thin film self-assembly offers an attractive alternative for producing periodic nanopatterns across large areas, yet the pattern feature sizes are fixed by the polymer molecular weight and composition. Here, a general strategy is reported which overcomes the limitation of the fixed feature size by treating the copolymer thin film as a hierarchical resist, in which the nanoscale pattern motif is defined by self-assembly. Feature sizes can then be tuned by thermal reflow controlled locally by irradiative cross-linking or chemical alteration using lithographic ultraviolet light or electron beam exposure. Using blends of polystyrene-block-poly(methylmethacrylate) (PS-b-PMMA) with PS and PMMA homopolymers, we demonstrate both self-assembled PS grating and hexagonal hole patterns; exposure-controlled reflow is then used to reduce the hole diameter by as much as 50% or increase the PS grating linewidth by more than 180%. Transferring these nanopatterns, or their inverse obtained by a lift-off approach, into silicon yields structural colors that may be prescriptively controlled based on the nanoscale feature size. Furthermore, patterned exposure enables area-selective feature size control, yielding uniform structural color patterns across centimeter square areas. Electron beam lithography is also used to show that the lithographic resolution of this selective-area control can be extended to the nanoscale dimensions of the self-assembled features. The exposure-controlled reflow approach demonstrated here takes a pivotal step toward fabricating complex, hierarchical optical metasurfaces using scalable self-assembly methods.

Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.

Tumor-associated macrophages (TAMs) exist in multiple phenotypes across the spectrum, defined by an M1 antitumorigenic phenotype and an M2 pro-tumorigenic phenotype on two ends of the spectrum. A largely immunosuppressive tumor-microenvironment aids the polarization of the infiltrating macrophages to a pro-tumorigenic M2 phenotype that promotes tumor progression and metastasis. Recent developments in macrophage immunotherapy have focused on strategies to re-educate TAMs from an M2 to M1 phenotype. Recent findings in the realm of immuno-metabolism have indicated that distinct metabolic signatures accompany macrophages based on their polarization states (M1-Glycolysis and M2-TCA cycle). These metabolites are important drivers of cellular signaling responsible for acquiring these polarization states, with evidence showing that metabolism is essential to facilitate the energy requirements of immune cells and regulate immune cell response. We hypothesized that TAMs could be reprogrammed metabolically by co-delivery of drugs using a supramolecular nanoparticle system that could effectively rewire macrophage metabolism by simultaneous inhibition of the TCA cycle and upregulation of the glycolytic metabolic pathway. TLR7/8 agonist and Fatty Acid Oxidation (FAO) inhibitor loaded metabolic supramolecular nanoparticles (MSNPs) were synthesized. In vitro assays showed macrophages treated with MSNPs were reprogrammed from an M2 phenotype to an M1 phenotype while significantly upregulating phagocytosis. When injected in 4T1 tumor-bearing mice, MSNPs treatment reduced tumor growth progression more than other treatments. Hence, the delivery of TLR7/8 agonist combined with an FAO inhibitor can enhance antitumor efficacy through metabolic reprogramming of tumor-associated macrophages.

Thin film block copolymer self-assembly for nanophotonics.

The nanophotonic engineering of light-matter interactions has profoundly changed research behind the design and fabrication of optical materials and devices. Metasurfaces-arrays of subwavelength nanostructures that interact resonantly with electromagnetic radiation-have emerged as an integral nanophotonic platform for a new generation of ultrathin lenses, displays, polarizers and other devices. Their success hinges on advances in lithography and nanofabrication in recent decades. While existing nanolithography techniques are suitable for basic research and prototyping, issues of cost, throughput, scalability, and substrate compatibility may preclude their use for many metasurface applications. Patterning via spontaneous self-assembly of block copolymer thin films offers an enticing alternative for nanophotonic manufacturing that is rapid, inexpensive, and applicable to large areas and diverse substrates. This review discusses the advantages and disadvantages of block copolymer-based nanopatterning and highlights recent progress in their use for broadband antireflection, surface enhanced Raman spectroscopy, and other nanophotonic applications. Recent advances in diversification of self-assembled block copolymer nanopatterns and improved processes for enhanced scalability of self-assembled nanopatterning using block copolymers are also discussed, with a spotlight on directions for future research that would enable a wider array of nanophotonic applications.

Tantalum Oxide as an Efficient Alternative Electron Transporting Layer for Perovskite Solar Cells.

Electron transporting layers facilitating electron extraction and suppressing hole recombination at the cathode are crucial components in any thin-film solar cell geometry, including that of metal-halide perovskite solar cells. Amorphous tantalum oxide (Ta2O5) deposited by spin coating was explored as an electron transport material for perovskite solar cells, achieving power conversion efficiency (PCE) up to ~14%. Ultraviolet photoelectron spectroscopy (UPS) measurements revealed that the extraction of photogenerated electrons is facilitated due to proper alignment of bandgap energies. Steady-state photoluminescence spectroscopy (PL) verified efficient charge transport from perovskite absorber film to thin Ta2O5 layer. Our findings suggest that tantalum oxide as an n-type semiconductor with a calculated carrier density of ~7 × 1018/cm3 in amorphous Ta2O5 films, is a potentially competitive candidate for an electron transport material in perovskite solar cells.

Imaging Approaches to Monitor Inflammasome Activation.

Inflammasomes are a critical component of innate immune response which plays an important role in the pathogenesis of various chronic and acute inflammatory disease conditions. An inflammasome complex consists of a multimeric protein assembly triggered by any form of pathogenic or sterile insult, resulting in caspase-1 activation. This active enzyme is further known to activate downstream pro-inflammatory cytokines along with a pore-forming protein, eventually leading to a lytic cell death called pyroptosis. Understanding the spatiotemporal kinetics of essential inflammasome components provides a better interpretation of the complex signaling underlying inflammation during several disease pathologies. This can be attained via in-vitro and in-vivo imaging platforms, which not only provide a basic understanding of molecular signaling but are also crucial to develop and screen targeted therapeutics. To date, numerous studies have reported platforms to image different signaling components participating in inflammasome activation. Here, we review several elements of inflammasome signaling, a common molecular mechanism combining these elements and their respective imaging tools. We anticipate that future needs will include developing new inflammasome imaging systems that can be utilized as clinical tools for diagnostics and monitoring treatment responses.

Core Hydrophobicity of Supramolecular Nanoparticles Induces NLRP3 Inflammasome Activation.

Designer nanomaterials capable of delivering immunomodulators to specific immune cells have been extensively studied. However, emerging evidence suggests that several of these nanomaterials can nonspecifically activate NLRP3 inflammasomes, an intracellular multiprotein complex controlling various immune cell functions, leading to undesirable effects. To understand what nanoparticle attributes activate inflammasomes, we designed a multiparametric polymer supramolecular nanoparticle system to modulate various surface and core nanoparticle-associated molecular patterns (NAMPs), one at a time. We also investigated several underlying signaling pathways, including lysosomal rupture-cathepsin B maturation and calcium flux-mitochondrial ROS production, to gain mechanistic insights into NAMPs-mediated inflammasome activation. Here, we report that out of the four NAMPs tested, core hydrophobicity strongly activates and positively correlates with the NLRP3 assembly compared to surface charge, core rigidity, and surface hydrophobicity. Moreover, we demonstrate different signaling inclinations and kinetics followed by differential core hydrophobicity patterns with the most hydrophobic ones exhibiting both lysosomal rupture and calcium influx early on. Altogether, this study will help design the next generation of polymeric nanomaterials for specific regulation of inflammasome activation, aiding efficient immunotherapy and vaccine delivery.

Rational combination of an immune checkpoint inhibitor with CSF1R inhibitor-loaded nanoparticle enhances anticancer efficacy.

Since the advent of immune checkpoint inhibitors, rapid strides have been made in the realm of cancer immunotherapy. Of the abundance of infiltrating immune cells in the tumor microenvironment (TME), macrophages contribute a significant portion and make up to 50% of the tumor mass. In addition to this, the relative plasticity of macrophages makes it an attractive target to modulate macrophage functions to initiate an anti-tumor response. However, many challenges hinder this strategy. Macrophage colony-stimulating factor (MCSF) secreted by cancer cells binds to the colony-stimulating factor receptor present on macrophages and negatively influences macrophage functions. MCSF, along with a cocktail of immunosuppressive cytokines present in the TME, polarizes macrophages to an immunosuppressive pro-tumorigenic M2-like phenotype. M2-like macrophages dampen tumor response and are known to be associated with increased tumor progression and metastasis. Indeed, clinical interventions aimed to reprogram macrophage response from an M2-like tumor aiding phenotype to an M1-like tumor-killing phenotype using small-molecule inhibitors of the CSF1R axis have gathered much attention in the recent past. However, poor response and systemic toxicities observed in these therapies necessitate alternative therapeutic strategies. Furthermore, another key signaling pathway that has been recently implicated in aiding the CSF1R signaling in TAMs is the PDL1 signaling axis. Hence, in this study, we designed a self-assembled lipid nanoparticle system encompassing a potent small-molecule inhibitor of the CSF1R signaling axis, while the surface of the nanoparticle was tethered with anti-PDL1 mAb. The purpose of this is twofold; the nanoparticles can deliver the cargo in a targeted manner to PDL1 expressing M2-like macrophages while simultaneously blocking the receptor. The resulting nanoparticle system termed α-PDL1-CSF-LNP showed enhanced repolarization of M2 like macrophages in vitro while also upregulating the phagocytic index. Furthermore, suboptimal dose administration of α-PDL1-CSF-LNP in an aggressive melanoma mouse model resulted in superior anti-tumor efficacy with minimal toxicities. These results were validated by ex vivo mechanistic analysis showing that TAMs have successfully been repolarized to a predominantly M1-like phenotype. This, along with increased tumor infiltration of CD8+ T cells, worked in synergy to provide an effective anti-tumor strategy.

Electrodeposition of atmosphere-sensitive ternary sodium transition metal oxide films for sodium-based electrochemical energy storage.

We introduce an intermediate-temperature (350 °C) dry molten sodium hydroxide-mediated binder-free electrodeposition process to grow the previously electrochemically inaccessible air- and moisture-sensitive layered sodium transition metal oxides, NaxMO2 (M = Co, Mn, Ni, Fe), in both thin and thick film form, compounds which are conventionally synthesized in powder form by solid-state reactions at temperatures ≥700 °C. As a key motivation for this work, several of these oxides are of interest as cathode materials for emerging sodium-ion-based electrochemical energy storage systems. Despite the low synthesis temperature and short reaction times, our electrodeposited oxides retain the key structural and electrochemical performance observed in high-temperature bulk synthesized materials. We demonstrate that tens of micrometers thick >75% dense NaxCoO2 and NaxMnO2 can be deposited in under 1 h. When used as cathodes for sodium-ion batteries, these materials exhibit near theoretical gravimetric capacities, chemical diffusion coefficients of Na+ ions (∼10-12 cm2⋅s-1), and high reversible areal capacities in the range ∼0.25 to 0.76 mA⋅h⋅cm-2, values significantly higher than those reported for binder-free sodium cathodes deposited by other techniques. The method described here resolves longstanding intrinsic challenges associated with traditional aqueous solution-based electrodeposition of ceramic oxides and opens a general solution chemistry approach for electrochemical processing of hitherto unexplored air- and moisture-sensitive high valent multinary structures with extended frameworks.

Engineered Multifunctional Nano- and Biological Materials for Cancer Immunotherapy.

Cancer immunotherapy is set to emerge as the future of cancer therapy. However, recent immunotherapy trials in different cancers have yielded sub-optimal results, with durable responses seen in only a small fraction of patients. Engineered multifunctional nanomaterials and biological materials are versatile platforms that can elicit strong immune responses and improve anti-cancer efficacy when applied to cancer immunotherapy. While there are traditional systems such as polymer- and lipid-based nanoparticles, there is a wide variety of other materials with inherent and additive properties that can allow for more potent activation of the immune system. By synthesizing and applying multifunctional strategies, it allows for a more extensive and more effective repertoire of tools to use in the wide variety of situations that cancer presents itself. Here, several types of nanoscale and biological material strategies and platforms that provide their inherent benefits for targeting and activating multiple aspects of the immune system are discussed. Overall, this review aims to provide a comprehensive understanding of recent advances in the field of multifunctional cancer immunotherapy and trends that pave the way for more diverse and tactical regression of tumors through soliciting responses by either the adaptive or innate immune system, and even both simultaneously.