Obesity is driven by chronic adipose tissue inflammation and macrophage dysfunction. Here, we report a cargo-free nanoparticle (NP) platform derived from itaconate-based polyesters (pITA-NPs) that reprograms macrophage immunometabolism and alleviates diet-induced obesity. pITA-NPs rapidly induce CD206 presentation through a translationally independent mechanism and drive a non-canonical M2-like transcriptional and metabolic state distinct from IL-4/STAT6 polarization, while restraining inflammatory activation and macrophage-adipocyte crosstalk to reduce lipid accumulation. Bioenergetic profiling revealed context-dependent metabolic tuning, with pITA-NPs promoting an M2-like metabolic transition in resting macrophages characterized by increased mitochondrial mass and oxidative phosphorylation, while inducing a metabolically restrained, quiescent-like state in M1-like macrophages. In obese mice, subcutaneous pITA-NP treatment suppresses weight gain, reduces adiposity, promotes adipose tissue beiging and brown fat activation, and mitigates systemic inflammatory responses. Together, these findings establish pITA-NPs as an effective immunometabolic nanotherapy that leverages materials-driven macrophage reprogramming and coordinates immune and metabolic regulation to treat obesity.

Septicemia remains a critical clinical challenge, even with conventional antibiotic therapies available. Severe infections signal opportunistic microbes to trigger overreactive immune responses, leading to the downward cascade of tissue damage and organ failure generally associated with sepsis. However, increasing multidrug antibiotic resistance further exacerbates the threat of these contaminations, emphasizing the need for therapeutics that act independently of targeting metabolic processes of the bacteria. Extracorporeal devices have been previously studied for their potential in blood cleansing therapies without the need for pathogen identification; however, apparatuses of this kind have not shown great success in translation to the physiological environment. Herein, we propose choline carboxylate ionic liquid-coated polymeric nanoparticles (IL-NPs) as a therapeutic for E. coli binding in whole blood, where the mechanism of action hinges on the IL-NPs labeling bacterial cells for an enhanced immune response to infection. IL-NPs maintain suitable red blood cell (RBC) hemocompatibility up to 40% v/v in both human and mouse blood, while the identity of the anionic moiety drives the selective bacterial binding. Treating E. coli with IL-NPs delays the initiation of the logarithmic growth phase due to the attachment of IL-NPs to the outer structures of the bacterial surfaces. The tunability of the ILs allows for the development of materials with preferential binding affinity toward E. coli cells and adaptable immune responses for the clearance of the captured microbes while maintaining minimal toxicity to mammalian cells. Future applications of the work discussed here will assess the efficacy of IL-NPs for bacterial labeling for enhanced pathogen removal in induced septicemic models in vivo.

The objective was to understand if sufficient base hydrolysis and subsequent small molecule quantitation within poly(lactic acid) nanoparticles (PLA-NPs) could be achieved using a mass spectrometry friendly volatile base, such as ammonium hydroxide. Additionally, we sought to evaluate the impact of NP formulation parameters on drug loading as assessed using liquid chromatography-tandem mass spectrometry (LC–MS/MS) quantitation. A microfluidics approach was used to create a library of NPs by systematically varying flow rate ratio (FRR; 1 or 3) and surfactant composition (poly(vinyl alcohol) or poly(glutamic acid)). NPs were characterized using dynamic light scattering to determine their size, polydispersity index, and zeta potential. Several hydrophobic drugs (NRX204647 and 7C, RARγ agonists; SF-7-044, p38α modulator) were tested for NP encapsulation. Base-catalyzed hydrolysis of PLA-NPs using either sodium hydroxide or ammonium hydroxide was employed to release encapsulated drug, which was then quantified using LC–MS/MS. Comparison of sodium hydroxide- and ammonium hydroxide-mediated base hydrolysis of PLA-NPs demonstrated that ammonium hydroxide was as effective for releasing encapsulated hydrophobic drugs for LC–MS/MS-based quantitative analysis. NP formulation parameters (FRR and surfactant chemistry) and drug physicochemical properties influenced NP characteristics and drug loading. Using a mass spectrometry friendly base for release of hydrophobic drugs encapsulated within PLA-NP is effective, enabling a simplified quantitative method to evaluate drug loading.

Allergic diseases affect an estimated 260 million people worldwide and develop due to dysregulated immune responses against harmless environmental antigens caused by a breakdown in immune tolerance mechanisms. Current standard-of-care treatments manage disease symptoms through nonspecific mechanisms impairing normal immune function, often leaving patients struggling with symptom management. Allergen-specific immunotherapies can modify the immune response by inducing tolerance, leading to long-term reduction or elimination of allergy symptoms. Recent advances in nanomedicine have opened new avenues of research to induce antigen-specific tolerance through the delivery of allergens alongside immunomodulators under controlled contexts. In this Special Report, we examine how nanomedicine and immunometabolism can be harnessed to develop next-generation therapies for allergic diseases. We first summarize current FDA-approved treatments and their limitations. We then discuss immunometabolic pathways that shape allergic inflammation and represent actionable therapeutic targets. Next, we review nanoparticle-based approaches designed to induce antigen-specific tolerance and highlight cutting-edge strategies that use metabolite-derived polymers for controlled immunomodulation. Finally, we offer a perspective on how integrating immunometabolism with nanomedicine may enable transformative therapies for allergic diseases and other inflammatory conditions. [PubMed and Google Scholar databases were searched for relevant articles published from May 2003 to January 2026].

Lipid nanoparticles (LNPs) have emerged as a versatile delivery platform for improving pharmacokinetic performance, protecting nucleic acid cargo, and enabling tissue- and cell-specific targeting. Continued advancement of LNP-based therapeutics requires a deeper understanding of how raw material quality, formulation parameters, nanoparticle architecture, and biological context collectively influence clinical performance. In this Perspective, we discuss key challenges, practical insights, and lessons learned from ongoing LNP development efforts, with emphasis on characterization strategies, delivery specificity, scale-up considerations, long-term stability, and emerging applications of artificial intelligence. We highlight the importance of rational design principles, robust and reproducible manufacturing practices, comprehensive analytical characterization, and innovative approaches to support the next generation of LNP technologies.

Lactoferrin (Lf) is a multifunctional endogenous glycoprotein with well-established antimicrobial and immunomodulatory activities. In this work, we report a modular nanoparticle (NP) platform in which Lf is engineered as a multilayered protein corona onto immunomodulatory poly(lactic-co-glycolic acid) NPs (PLGA@Lf). By integrating the intrinsic anti-inflammatory properties of PLGA NPs with the diverse bioactivities of Lf, this hybrid corona design enables concurrent immune activation and suppression while enhancing antibacterial functionality. We demonstrate that Lf stably adsorbs onto PLGA NPs in a concentration-dependent manner, altering particle size and zeta potential consistent with multilayered corona formation. PLGA@Lf was shown to stimulate innate immune cells, enhancing Escherichia coli bioparticle phagocytosis, while simultaneously reducing pro-inflammatory cytokine levels in lipopolysaccharide (LPS)-challenged macrophages. Further antimicrobial activity studies demonstrated robust inhibition of bioluminescent E. coli activity in vitro. Lastly, in an in vivo therapeutic LPS-induced endotoxemia model, PLGA@Lf significantly reduced plasma levels of TNF-α compared to uncoated controls, highlighting their enhanced anti-inflammatory properties. Collectively, these results establish PLGA@Lf NPs as a dual-function nanomaterial platform that efficiently balances both immune stimulation and suppression responses, offering a promising strategy for managing infectious and inflammatory diseases.

Obesity represents a global health crisis characterized by chronic adipose tissue (AT) inflammation (metaflammation) driven by pro-inflammatory M1 macrophage (MΦ) polarization, adipocyte hypertrophy, and impaired thermogenic capacity of white adipose tissue (WAT). While interleukin-4 (IL-4) potently induces M2 MΦ polarization, its clinical translation is limited by poor stability, rapid clearance, and off-target effects. Here, we engineered lipid nanoparticles (IL-4/LNP) via simple, robust thin-film hydration and extrusion to enable sustained IL-4 delivery to MΦs in inflamed AT. In vitro, IL-4/LNP achieved >70% encapsulation efficiency, a uniform ∼150 nm size, and superior M1 to M2 MΦ reprogramming compared with free IL-4, as evidenced by CD206 upregulation, reduced CD80/CD40 expression, and attenuated TNF-α/IL-6 secretion in LPS-stimulated MΦ. In adipocyte-mimicking cells (3T3-L1)-MΦ co-cultures representing white and brown adipose tissue (BAT), paracrine signaling from IL-4/LNP-polarized M2 MΦs drove a profound reduction in lipid droplets (LDs) and beiging, with decreased Feret diameter and integrated optical density. Using a high-fat diet-induced obese mouse model, localized inguinal/visceral AT injections blunted weight gain by ∼10%, induced multilocular beige-like adipocytes across depots, upregulated thermogenic genes (Ucp1 and Pgc1α), downregulated inflammatory markers (IL-6), and improved hepatic steatosis without systemic toxicity. These findings establish IL-4/LNP as a safe, multifunctional platform that links MΦ immunomodulation and adipose browning in obesity therapy. STATEMENT OF SIGNIFICANCE: This study establishes IL-4-loaded lipid nanoparticles (IL-4/LNPs) as a nanomedicine platform that targets the immunometabolic roots of obesity by reprogramming adipose tissue macrophages and promoting white fat browning. IL-4/LNPs are produced by a simple, scalable thin-film hydration-extrusion method, yielding ∼150 nm particles with ∼73% encapsulation, suitable for local adipose delivery. In vitro, the NPs outperform free IL-4 by enhancing M2 polarization, driving paracrine adipocyte remodeling, and reducing lipid burden in 3T3-L1 co-cultures. In high-fat diet-obese mice, depot-specific IL-4/LNP injections limit weight gain, induce adipocyte beiging, improve hepatic steatosis, and reduce systemic inflammation without detectable toxicity, supporting IL-4/LNPs as a translatable cytokine nanotherapy for metaflammatory obesity.

Motivated by promising clinical trial data for the combination of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat with the proteasome inhibitor bortezomib in relapsed/refractory multiple myeloma (MM) patients, we engineered dual HDAC6/proteasome inhibitors. FDA-approved HDAC inhibitors suffer from off-target effects, which have been attributed, in part, to their lack of HDAC isoform selectivity. Furthermore, they are potentially mutagenic, because of their indispensable hydroxamic acid zinc-binding groups (ZBGs). Deploying the HDAC6-selective phenyl-4-hydroxamic acid motif, and O-carbamoylated hydroxamates as hydroxamic acid surrogates, then grafting to the electrophilic boronic acid warhead of bortezomib/ixazomib, we discovered several dual HDAC6/proteasome inhibitors that were potent in cell-free assays, inhibiting the chymotrypsin-like (CL) proteasomal activity on par with that of bortezomib, and many compounds demonstrated selectivity for HDAC6 over HDAC1 as predicted. Moreover, several dual HDAC6/proteasome inhibitors were submicromolar inhibitors of MM cell growth. Of particular interest, AMC-3-030 with an O-(N-phenylcarbamoyl)-hydroxamate ZBG emerged as an exciting lead for further studies.

Polymeric nanoparticles (NPs) are promising tools used for immunomodulation and drug delivery in various disease contexts. The interaction between NP surfaces and plasma-resident biomolecules results in the formation of a biomolecular corona, which varies patient-to-patient and as a function of disease state. This study investigates how the progression of acute systemic inflammatory disease influences NP corona compositions and the corresponding effects on innate immune cell interactions, phenotypes, and cytokine responses. NP coronas alter cell associations in a disease-dependent manner, induce differential co-stimulatory and co-inhibitory molecule expression, and influence cytokine release. Integrated multi-omics analysis of proteomics, lipidomics, metabolomics, and cytokine datasets highlight a set of differentially enriched TLR4 ligands that correlate with dynamic NP corona-mediated immune activation. Pharmacological inhibition and genetic knockout studies validate that NP coronas mediate this response through TLR4/MyD88/NF-κB signaling. Our findings illuminate the personalized nature of corona formation under a dynamic inflammatory condition and its impact on NP-mediated immune activation profiles and inflammation, suggesting that disease progression-related alterations in plasma composition can manifest in the corona to cause unintended toxicity and altered therapeutic efficacy.

Obesity is characterized by a significant imbalance in adipose tissue macrophages (ATMs), shifting from anti-inflammatory M2 to pro-inflammatory M1 phenotypes, contributing to chronic low-grade inflammation and metabolic dysfunction. This study explores the potential of nanoparticle (NP)-mediated immunomodulation to address obesity-related inflammation, adipocyte browning, and metabolic dysfunction. Apigenin (Api), a natural compound with notable anti-inflammatory properties, was encapsulated within poly(lactic-co-glycolic acid) (PLGA) NPs (Api-NPs) for localized delivery to adipose tissues (ATs). Api-NPs demonstrated favorable physicochemical properties and sustained release profiles. In vitro, Api-NPs, increased M2 macrophage (MΦ) polarization, reduced inflammatory markers, and promoted adipocyte browning. In a high-fat diet (HFD)-induced obesity mouse model, Api-NP administration effectively modulated MΦ polarization and enhanced AT browning, leading to marked reductions in body weight and AT mass. Our findings indicate that Api-NP treatment mitigates obesity-related inflammation and promotes beneficial changes in AT composition and function. Importantly, histological evaluations confirmed the absence of toxicity in major organs, reinforcing the safety profile of this approach. These results position Api-NPs as a promising novel therapeutic strategy for obesity management, integrating immune modulation and localized drug delivery to address the complexities of obesity and its associated inflammatory processes.

Obesity has emerged as a global epidemic, posing severe challenges to public health and contributing to various complications, including metabolic disorders, cardiovascular disease, and type 2 diabetes. This review provides a comprehensive overview of obesity, its associated comorbidities, and the limitations of conventional treatments. We explore the complex relationship between obesity-induced inflammation, immune dysregulation, and the pivotal role of adipose tissue macrophages (ATMs). Chronic low-grade inflammation in adipose tissues (AT) is a key driver of insulin resistance and metabolic dysfunction. As ATs expand, they undergo significant changes, including increased immune cell infiltration, particularly macrophages (MΦs), which shift from an anti-inflammatory towards a pro-inflammatory phenotype. This review aims to advance the understanding of immunomodulatory strategies by examining MΦ polarization and AT browning as promising therapeutic approaches. We focus on nanoparticles (NPs)-based strategies for immunomodulation, highlighting innovative engineering approaches designed to target the inflammatory pathways underlying obesity. By addressing these mechanisms, this review provides valuable insights into mitigating obesity-associated inflammation and related metabolic disorders, paving the way for novel therapeutic strategies in the fight against the global obesity epidemic.

Polymeric nanoparticles (NPs) are traditionally formulated using batch methodologies that are poorly scalable and require time consuming, hands-on purification procedures. Here, we prepared poly(lactic acid) (PLA)-based polymeric NPs using a scalable microfluidics-based method and systematically investigated the impact of purification method (centrifugation versus tangential flow filtration (TFF)) to remove poly(vinyl alcohol) (PVA) on macrophage uptake, anti-inflammatory effects, biodistribution, and protein corona formation. TFF purification demonstrated significantly higher recovery of NPs compared to the centrifugation method, with little-to-no aggregation observed. PVA removal efficiency was superior with centrifugation, although TFF was comparable. NP cellular association, in vitro anti-inflammatory activity, and in vivo biodistribution studies suggested purification method-dependent alterations, which were correlated with protein corona profiles. This study underscores the potential of TFF, combined with microfluidics, as an efficient and high-yield purification method for NPs, and reveals the need for extensive confirmation of NP biological activity alongside physicochemical properties when developing NP therapeutics at-scale.

Plant-derived lipid nanoparticles (PDNPs) are nano-sized particles isolated from various edible plants that contain bioactive components involved in regulating biological responses. Here, we isolated maca-derived lipid nanoparticles (MDNPs) from Lepidium meyenii Walp (maca), evaluated their therapeutic effects using two representative lethal models of sepsis, and determined their multimodal anti-inflammatory mechanism that relied on broad sequestration and neutralization of multiple pro-inflammatory cytokines and acute phase proteins (APPs) through formation of a protein corona. Lipidomics of MDNPs revealed triacylglycerols and phytoceramides as major constituents. In vitro studies showed that MDNPs were non-toxic, reduced macrophage activation, and sequestered lipopolysaccharide (LPS)-induced pro-inflammatory cytokines, while mitigating nuclear factor kappa B (NF-κB) activity. In a pre-established LPS-induced endotoxemia model, MDNP treatment significantly reduced systemic pro-inflammatory cytokines, reduced organ damage, and increased survival. Untargeted proteomics and bioinformatics analysis identified an enrichment in APPs present in MDNP protein coronas and corresponding inflammatory pathways modulated. The efficacy of MDNPs were further tested using a lethal polymicrobial sepsis model, where treatment significantly improved survival even in the absence of antibiotics. This study identifies MDNPs as an effective strategy capable of inducing potent anti-inflammatory responses, offering significant therapeutic potential for diseases such as sepsis, while informing the future design of synthetic lipid nanoparticles.

Obesity is defined as chronic, low-grade inflammation within specific tissues. Given the escalating prevalence of obesity among individuals of all ages, obesity has reached epidemic proportions, posing an important public health challenge. Despite significant advancements in treating obesity, conventional approaches remain largely ineffective or involve severe side effects, thus underscoring the pressing need to explore and develop treatment approaches. Targeted and local immunomodulation using nanoparticles (NPs) can influence fat production and utilization processes. Statins, known for their anti-inflammatory properties, show the potential for mitigating obesity-related inflammation. A localized delivery option offers several advantages over oral and parenteral delivery methods. Here, we developed simvastatin (Sim) encapsulated within PLGA NPs (Sim-NP) for localized delivery of Sim to adipose tissues (ATs) for immunomodulation to treat obesity. In vitro experiments revealed the strong anti-inflammatory effects of Sim-NPs, which resulted in enhanced modulation of macrophage (M Phi) polarization and induction of AT browning. We then extended our investigation to an in vivo mouse model of high-fat-diet (HFD)-induced obesity. Sim-NP administration led to the controlled release of Sim within AT, directly impacting M Phi activity and inducing AT browning while inducing weight loss. Our findings demonstrated that Sim-NP administration effectively inhibited the progression of obesity-related inflammation, controlled white fat production, and enhanced AT modulation. These results highlight the potential of Sim-NP as a potent nanotherapy for treating obesity by modulating the immune system.

Allergic disease is a major global health concern that imposes significant life-altering and economic burdens on affected individuals. However, there is still no cure. Polymer-based nanoparticles (NP) have shown the potential to induce antigen (Ag)-specific immune tolerance in various Th1/17 and Th2-mediated immune disorders including autoimmunity and allergy. Common methods by which Ags are associated with NPs are through surface conjugation or encapsulation. However, these Ag delivery strategies can be associated with several caveats that dampen their effectiveness such as uncontrolled Ag loading, a high Ag burst release, and an increased immune recognition profile. We previously developed Ag-polymer conjugate NPs (acNPs) to overcome those noted limitations, while allowing for controlled delivery of precise quantities of Ag to innate immune cells for Ag-specific CD4 T cell modulation. Here, we utilized ovalbumin (OVA) protein-poly(lactic-co-glycolic acid) (PLGA) conjugate NPs (acNP-OVA) to elucidate the impact of Ag loading on the induction of Th2 tolerance using a prophylactic and therapeutic OVA/ALUM-induced mouse model of allergic lung inflammation (ALI) in comparison to Ag-encapsulated PLGA NPs (NP(Ag)). We demonstrate that acNP-OVA formulations reduced OVA-specific IgE and inhibited Th2 cytokine secretions in an Ag loading-dependent manner when administered prophylactically. Administration of acNP-OVA to pre-sensitized mice did not affect OVA-specific IgE and Th2 cytokines tended to be reduced, however, there was no clear Ag loading dependency. acNP-OVA with medium-to-low Ag loadings were well tolerated, while formulations with high Ag loadings, including NP(Ag) resulted in anaphylaxis. Overall, our results clarify the relationship between Ag loading and Ag-specific IgE and Th2 cytokine responses in a murine model of ALI, which provides insight useful for future design of tolerogenic NP-based immunotherapies.

Polymeric nanoparticles (NPs) comprised of poly(lactic-co-glycolic acid) (PLGA) have found success in modulating antigen (Ag)-specific T cell responses for the treatment multiple immunological diseases. Common methods by which Ags are associated with NPs are through encapsulation and surface conjugation; however, these methods suffer from several limitations, including uncontrolled Ag loading, burst release, and potential immune recognition. To overcome these limitations and study the relationship between NP design parameters and modulation of innate and Ag-specific adaptive immune cell responses, we developed ovalbumin (OVA) protein-PLGA bioconjugate NPs (acNP-OVA). OVA was first modified by conjugation with multiple PLGA polymers to synthesize OVA-PLGA conjugates, followed by precise combination with unmodified PLGA to form acNP-OVA with well-defined Ag loadings, reduced burst release, and reduced antibody recognition. Expression of MHC II, CD80, and CD86 on bone marrow-derived dendritic cells (BMDCs) increased as a function of acNP-OVA Ag loading. NanoString studies using BMDCs showed that PLGA NPs generally induced anti-inflammatory gene expression profiles independent of the Ag delivery method, where S100a9, Sell, and Ppbp were most significantly reduced. Co-culture studies using acNP-OVA-treated BMDCs and OT-II CD4+ T cells revealed that Ag-specific T cell activation, expansion, and differentiation were dependent on Ag loading and formulation parameters. CD25 expression was induced using acNP-OVA with the lowest Ag loading; however, the induction of robust CD4+ T cell proliferative and cytokine responses required acNP-OVA formulations with higher Ag loading, which was supported using a regulatory T cell (Treg) induction assay. The distinct differences in Ag loading required to achieve various T cell responses supported the concept of an Ag loading threshold for Ag-specific immunotherapy. We anticipate this work will help guide NP designs and aid in the future development of NP-based immunotherapies for Ag-specific immunomodulation.