Every entry summarises what the study set out to test, what it found and why it changes how we design delivery systems. Browse research and reviews or search the collection.
Hamideh Parhiz, Jacob S. Brenner, Priyal N. Patel, Tyler E. Papp, Hamna Shahnawaz, Qin Li, Ruiqi Shi, Marco E. Zamora, Amir Yadegari, Oscar A. Marcos-Contreras, Ambika Natesan, Norbert Pardi, Vladimir V. Shuvaev, Raisa Kiseleva, Jacob W. Myerson, Thomas Uhler, Rachel S. Riley, Xuexiang Han, Michael
Nucleoside-modified mRNA lipid nanoparticle (modmRNA-LNP) technology is clinically successful, but its behavior in pre-existing inflammatory or immune-challenged conditions is poorly characterized. This gap raises the risk of adverse effects when modmRNA-LNPs are administered to patients with ongoing inflammation. IE with LPS + modmRNA-LNP: Serum IL-6 increased 14-fold vs LPS alone and 94-fold vs modmRNA-LNP in naive mice. Liver MIP-2 increased 11-fold vs LPS alone and 52-fold vs modmRNA-LNP in naive mice. Liver MIP-2 mRNA.
Martijn J.W. Evers, Wenjuan Du, Qiangbing Yang, Sander A.A. Kooijmans, Aryan Vink, Mies Van Steenbergen, Pieter Vader, Saskia C.A. De Jager, Sabine A. Fuchs, Enrico Mastrobattista, Joost P.G. Sluijter, Zhiyong Lei, Raymond Schiffelers
Modified mRNA (modRNA) is a promising cardiac regeneration therapeutic, but naked mRNA is large, negatively charged, and rapidly degraded. It is unknown whether systemically administered lipid nanoparticles (LNPs) can functionally deliver mRNA to ischemic/damaged myocardium after myocardial infarction. LNPs were <100 nm with PDI <0.2 and 95–99% mRNA encapsulation. - After ischemia-reperfusion, fluorescent LNPs accumulated in the infarcted area of the heart at 4 h and 24 h, but not in sham or control hearts. -.
Hanwen Zhang, Xuexiang Han, Mohamad-Gabriel Alameh, Sarah J. Shepherd, Marshall S. Padilla, Lulu Xue, Kamila Butowska, Drew Weissman, Michael J. Mitchell
LNPs can trigger innate immune responses and inflammation, which can suppress mRNA translation and cause adverse effects. There is a need for LNP formulations that reduce LNP-induced inflammation while maintaining or improving mRNA delivery. C9D1 and C10D0 had similar size, PDI, and >90% mRNA encapsulation; Dex substitution did not impair in vitro transfection or increase cytotoxicity. - Higher Dex substitution (C7D3, C5D5, C3D7, C0D10) reduced.
Randall A. Meyer, Sarah Y. Neshat, Jordan J. Green, Jose Luis Santos, And Anthony D. Tuesca
mRNA gene therapy has broad therapeutic potential (protein replacement, vaccines, regenerative medicine, oncology), but clinical translation is limited by inadequate understanding of how to target specific organs or cell types for protein expression. Reports on material properties and administration routes are disparate, preventing a global understanding of how these factors contribute to organ targeting for mRNA delivery. Liver targeting: LNPs intrinsically target liver via ApoE-mediated uptake through LDLR. Optimized ionizable lipids increased liver luciferase expression 18-fold. Oxidized cholesterol variants improved protein expression.
Glioblastoma (GBM) is one of the deadliest primary adult tumors with a median survival of only 14.6 months post-diagnosis, a statistic that has changed little in two decades. While cancer immunotherapy has shown remarkable progress in other solid tumors, the blood-brain barrier (BBB) and the immune-privileged status of the central nervous system pose unique drug delivery obstacles. A comprehensive understanding of physiological, immunological ### Transport Barriers | **Barrier** | **Key Finding** | |-------------|-----------------| | BBB | Passive transport limited to <400 Da or lipid-soluble molecules; all GBM patients have tumor regions with.
Julia Koerner, Dennis Horvath, Valerie L. Herrmann, Anna Mackeracher, Bruno Gander, Hideo Yagita, Jacques Rohayem, Marcus Groettrup
Cancer immunotherapy needs potent, pharmaceutically defined, GMP-compatible adjuvants for clinical translation. Poly(I:C) is a widely used TLR3 agonist but has ill-defined structure, heterogeneity, pyrogen contamination, and toxicity concerns. Riboxxim is a well-defined 100-bp double-stranded RNA with a 5′-triphosphate moiety that activates both endosomal TLR3 and cytosolic RIG-I. PLGA particles can co-deliver antigen and adjuvant to dendritic. Particle properties: MPs ~1–1.5 µm; NPs ~250 nm; negative zeta potential; OVA release burst within 24 h followed by sustained release. MPs showed better release profile than NPs. - Route comparison: Subcutaneous.
Tumor microenvironment (TME) modulation is a promising strategy in cancer immunotherapy, but conventional immunotherapeutic agents suffer from limited drug retention in the TME, severe adverse events, and low response rates. Nanoparticles can prolong retention, enable targeted delivery to TME components, and convert the immunosuppressive TME into an immunosupportive state, potentially improving therapeutic efficacy while reducing toxicity. DC targeting: CD40-targeted PLGA nanoparticles achieved highest binding/uptake and maximum IL-12 production in vitro; however, T cell proliferation was driven mainly by TLR ligands rather than targeting ligand. -.
John C. Charpentier, Di Chen, Philip E. Lapinski, Jackson Turner, Irina Grigorova, Joel A. Swanson, Philip D. King
Macropinocytosis has been shown to regulate the growth of Ras-transformed tumor cells under amino acid (AA)-limiting conditions by providing extracellular proteins that are degraded into AA to fuel cell growth and activate mTORC1. However, whether macropinocytosis regulates the growth of non-transformed mammalian cells, such as primary T lymphocytes, was unknown. Understanding whether macropinocytosis is required for T cell growth has. ### T Cell Macropinocytosis (Probe Uptake) | Cell Type | Probe | Stimulation | Fold Increase (Stimulated vs. Unstimulated) |.
Dylan J. Drakes, Sarwish Rafiq, Terence J. Purdon, Andrea V. Lopez, Smita S. Chandran, Christopher A. Klebanoff, Renier J. Brentjens
T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation in vivo, particularly when tumor cells downregulate costimulatory molecules. A method to provide a durable proinflammatory signal to TCR-modified T cells could enhance persistence, effector. ### In Vitro T Cell Activation & Cytotoxicity | Parameter | Control | mIL12 pmel-1 | mIL18 pmel-1 | |---------------|-------------|------------------|------------------| | IFNγ secretion | Baseline | Significantly.
In vivo engineering of T lymphocytes is limited by poor transfection efficiency and reliance on ex vivo electroporation. A non-viral mRNA delivery platform that can target primary T cells in vivo is needed for CAR T-cell therapy, vaccines, and immunotherapy. Rough screening identified imidazole head 93 with O17O, O17S, and O17Se tails as effective for mRNA delivery to primary T cells; Lipofectamine 2000 was poor. - Detailed screening identified 93-O17S and 9322-O17S as top.
Tumor-associated macrophages (TAMs) are largely M2-like and promote tumor growth, angiogenesis, metastasis, and immune suppression. There is a need for systemic delivery systems that can target TAMs and manipulate their pro-tumor functions with siRNA for cancer immunotherapy. Optimized CL4H6-LNPs had >90% siRNA encapsulation efficiency, neutral surface charge, and 90–100 nm size. - DSG-PEG2000 modification increased tumor accumulation 1.74-fold compared with DMG-PEG2000. - TAM uptake was.
Elana Ben-Akiva, Randall A. Meyer, Hongzhe Yu, Jonathan T. Smith, Drew M. Pardoll, Jordan J. Green
Previous red blood cell (RBC) membrane-coated nanoparticles have all been spherical, missing the physical shape component of biomimicry. Particle shape is a critical design parameter affecting biodistribution, macrophage evasion, and targeted interactions. A platform combining physical biomimicry (anisotropic shape) with chemical biomimicry (RBC membrane coating) could improve circulation time and detoxification efficacy. Macrophage uptake: RBC membrane coating reduced uptake by 30–50%; anisotropic shape reduced uptake by 30–40%; combined coating + anisotropy reduced uptake by 50–70% versus spherical uncoated particles at 4 h. - Blood.
DNA vaccines require high doses because naked DNA is poorly delivered to antigen-presenting cells (APCs), and conventional PLGA microsphere encapsulation by W/O/W emulsion can damage DNA, lower supercoiled DNA content, and give low encapsulation efficiency. A controlled-release system is needed that protects DNA during formulation and enhances immunogenicity at lower doses. Polyplex characterization: PEG-g-PEI/DNA polyplexes at N/P = 20 had a size of 74.1 ± 21.2 nm and zeta potential of 11.47 ± 0.78 mV; transfection peaked at N/P ≥ 20, and cell viability was >90% at N/P ≤ 20. - NIM.
Francesca Giulimondi, Luca Digiacomo, Daniela Pozzi, Sara Palchetti, Elisabetta Vulpis, Anna Laura Capriotti, Riccardo Zenezini Chiozzi, Aldo Laganà, Heinz Amenitsch, Laura Masuelli, Giovanna Peruzzi, Morteza Mahmoudi, Isabella Screpanti, Alessandra Zingoni
Liposome clinical translation is limited by opsonization and rapid clearance by immune cells. Although the protein corona is recognized as the liposome’s “biological identity,” it was unclear whether pre-adsorbed corona proteins could help liposomes avoid capture by circulating leukocytes in whole blood and thereby prolong blood residency. Zeta potential: At high HP, zeta potential of DOTAP, DOPC, and DOPG converged to a common negative plateau of ~ −23 mV, independent of pristine surface charge. - Size: DOTAP size increased at low HP, peaked near charge.
Biomaterials and nanoparticles (NPs) used for medical purposes often trigger immune recognition, inflammation, and rapid clearance by the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS). PEGylation and cell-membrane camouflaging are common stealth strategies, but they have limitations, including anti-PEG immune responses. CD47, a “don’t-eat-me” signal, is emerging as an alternative stealth functionalization to improve. CD47-coated polystyrene beads reduced macrophage phagocytosis by 50% compared with CD47-free beads; anti-CD47 antibody abolished the effect. - CD47 immobilization on PVC tubing almost completely inhibited cell.
Jayoung Kim, James G. Shamul, Sagar R Shah, Alyssa Shin, Ben J Lee, Alfredo Quiñones‐hinojosa, Jordan J. Green
Many anticancer small molecules have poor aqueous solubility, and verteporfin (VP) has mainly been used as a photodynamic therapy agent, which carries photosensitivity and delivery limitations. PBAE-based materials have been developed extensively for nucleic acid delivery but are less explored for non-genetic hydrophobic drug delivery. There is a need for biodegradable, pH-sensitive micelles that can encapsulate VP and potentially evade. CMC: PP1 micelles formed at 0.056 mg/mL. - Macrophage uptake: fVPM showed an 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean uptake compared with sVPM in RAW 264.7 macrophages. -.
Lopes Rm, Gaspar Mm, Pereira J, Eleuterio Cv, Carvalho M, Almeida Aj, Cruz Mem
Current leishmaniasis chemotherapy lacks options that combine high activity, low toxicity, and affordable cost. Oryzalin (ORZ), a dinitroaniline with in vitro antileishmanial activity, is limited by poor water solubility and low accumulation in diseased organs. Lipid-based nanocarriers may overcome these limitations, but liposomes and solid lipid nanoparticles had not been systematically compared as ORZ carriers. Formulation: Lip-ORZ ~0.21 µm, ζ ~ −30 to −35 mV, incorporation efficiency 91–94%. LNP-ORZ ~0.17 µm, ζ ~ −22 to −24 mV, incorporation efficiency 95–97%. - In vitro toxicity: Free ORZ: HC₅₀ 425 µM, CC₅₀ 20 µM. Lip-ORZ.
Slavomíra Doktorovová, Eliana B. Souto, Amélia Maria Silva
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were developed as alternative colloidal carriers with better stability and tolerability than polymeric nanoparticles. However, in vitro toxicity data were scattered across many cell lines, assays, exposure times, concentrations, and formulations, with some contradictory results. A systematic review was needed to consolidate cytotoxicity, oxidative stress, genotoxicity, and. Most reported IC50 values for blank SLN/NLC were in the range 0.1–1.0 mg/mL; some formulations had IC50 >1 mg/mL, and a few were more toxic. - PVA and SDS as surfactants were associated with low IC50 values; Tween 80.
Extracellular miRNAs are unusually stable in plasma and their circulating levels change with disease, making them promising biomarkers. They are associated with lipid-based carriers—exosomes, microvesicles, apoptotic bodies, and lipoproteins—as well as lipid-free proteins. Whether these carriers mediate functional miRNA transfer between cells and act as a form of intercellular communication was the central gap addressed. Over 1,500 human miRNAs have been curated; each cell type typically contains ~150–300 miRNAs. - HDL was shown to contain miRNAs and deliver them to Huh7 hepatocellular carcinoma cells and SR-BI–overexpressing BHK cells.
DNA vaccines can induce antibody and CTL responses, but clinical translation is limited by weak potency and the need for high or repeated doses. The study addresses this by targeting DNA to antigen-presenting cells (APCs) and improving endosomal/lysosomal release, using mannose-bearing chitosan microspheres loaded with PEI/DNA complexes for an HBV DNA vaccine. Microsphere characterization: m-chitosan microspheres were 326.3 ± 31.9 nm, with 89 ± 2.6% DNA encapsulation efficiency and zeta potential 10.19 ± 3.23 mV. u-chitosan microspheres were 415.2 ± 44.2 nm, 94 ± 5.4%.
Daqing Wang, Deborah R. Robinson, Glen S. Kwon, John Samuel
Naked plasmid DNA vaccination is largely limited to intramuscular, cutaneous, and intradermal routes because naked DNA is ineffective at crossing mucosal barriers and is rapidly degraded by nucleases. Delivery systems that protect plasmid DNA and target it to antigen-presenting cells are needed for mucosal DNA vaccines and broader immunogene delivery. Encapsulation efficiency increased with PLGA molecular mass: 22.5% at 6,000 Da, 30.0% at 12,500 Da, 50.7% at 30,000 Da, and 53.3% at 50,000 Da. DNA loading ranged from 0.62 to 1.41 µg/mg PLGA. - Structural and.
Hans-Jörg Heiniger, Arnold Sodergren, Jan D. Marshall
While pinocytosis (endocytosis) in lymphocytes had been qualitatively described using electron microscopy, quantitative measurements of endocytic activity and its relationship to immunological function were lacking. Understanding whether endocytosis correlates with T cell differentiation and cytotoxic function is important because immunocompetent cells exert their biological functions through plasma membrane interactions with their environment. ### Endocytic Rate in Primary MLC (Day 1-11) | Day | Endocytic Rate (ng HRP/hr/10⁶ cells) | Relative Activity | |---------|------------------------------------------|----------------------| | Day 1 | Very low | Baseline.
Kevin J. Kauffman, Clement Do, Sadhana Sharma, Matthew D. Gallovic, Eric M. Bachelder, Kristy M. Ainslie
Acetalated dextran (Ac-DEX) is a pH-sensitive, biodegradable polymer useful for drug delivery, but it degrades to methanol, which can be toxic at high concentrations or with repeated dosing. A safer analog that degrades to ethanol instead of methanol is needed for high-volume clinical applications such as multiple dosing and tissue engineering. Polymer synthesis: ¹H NMR confirmed ethanol and acetone as degradation products; methanol peak was absent. - Acetal coverage: Acyclic acetal coverage decreased logarithmically with reaction time; cyclic acetal coverage.
