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.
Hannah J Vaughan, Camila G Zamboni, Kathryn M Luly, Ling Li, Kathleen L Gabrielson, Laboni F Hassan, Nicholas P Radant, Pranshu Bhardwaj, Florin M Selaru, Martin G Pomper, Jordan J Green
Hepatocellular carcinoma (HCC) has limited treatment options, with modest survival after systemic chemotherapy or transarterial chemoembolization (TACE). Gene therapies hold promise for treating HCC, but delivery remains a critical hurdle. While poly(beta-amino ester) (PBAE) nanoparticles have shown efficacy in transfecting HCC cells, their delivery via locoregional routes—specifically intra-arterial injection—had not been investigated, despite. ### In Vitro Transfection (N1-S1 Rat HCC Cells) | Parameter | Result | |---------------|------------| | Transfection efficiency (all PBAEs) | >50% GFP+ cells at various doses and w/w ratios | | Cell viability | >70% for.
Bispecific T-cell engagers (BiTEs) are promising but require large amounts of purified protein, have high manufacturing costs, poor in vivo stability, and short serum half-lives. mRNA delivery could enable continuous endogenous production of BiTEs, but efficient and safe delivery systems are needed. The study developed a novel ionizable lipid nanoparticle (LNP) for mRNA encoding B7H3×CD3 BiTE to achieve prolonged half-life and potent antitumor. LNP@GFP-mRNA showed transfection efficiency comparable to Lipofectamine 8000 in 293T, AML12, and LO2 cells; serum presence did not affect transfection. - After IV LNP@Luc-mRNA, strongest luciferase signal was in liver.
Xuexiang Han, Ningqiang Gong, Lulu Xue, Margaret M. Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh, Drew Weissman, Michael J. Mitchell
Liver fibrosis has no approved antifibrotic therapies. Activated hepatic stellate cells (HSCs) drive fibrosis by producing collagen, and HSP47 is a key collagen chaperone in these cells. Targeted delivery of siRNA to activated HSCs remains challenging, so a ligand-tethered LNP platform was developed to deliver RNA selectively to activated fibroblasts/HSCs. Lead AA-T3A-C12 LNP achieved >80% GFP knockdown at 50 nM in activated 3T3-GFP fibroblasts; knockdown significantly reduced by haloperidol (p = 0.009), confirming sigma receptor dependence. - In fibroblast/hepatocyte.
Yulia Eygieris, Mohit Gupta, Jeonghwan Kim, Gaurav Sahay
LNPs enabled the COVID-19 mRNA vaccines and the first siRNA-LNP drug, but there is still no one-size-fits-all LNP for every RNA therapeutic. A better chemistry-level understanding of LNP self-assembly, component roles, and whole-particle properties is needed to rationally design safer and more efficient RNA delivery systems. ## 3. Hypothesis / Central Thesis LNP performance is governed by the coordinated chemistry of ionizable lipids, sterols Ionizable lipids typically have tertiary amine headgroups and biodegradable ester linkers; cpKa ~9–10.5, LNP pKa ~6–7, and cLogD ~10–14 are associated with potency. - Cholesterol analogues can strongly.
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. -.
Savan K. Patel, Margaret M. Billingsley, Caitlin Frazee, Xuexiang Han, Kelsey L. Swingle, Jingya Qin, Mohamad-Gabriel Alameh, Karin Wang, Drew Weissman, Michael J. Mitchell
mRNA delivery to T cells could enable ex vivo and in vivo T cell engineering, but LNPs still face poor extrahepatic delivery, endosomal recycling, and limited T cell transfection. Cholesterol analogs such as hydroxycholesterols may alter NPC1 recognition and endosomal trafficking, providing a route to improve T cell mRNA delivery. In primary human T cells, A1-25 and A1-50 improved mRNA delivery by 1.8-fold and 2.0-fold, respectively, vs S2. - In Jurkat cells, A1-25, A1-50, and B1-50 increased luciferase expression 2.1-fold, 1.9-fold, and.
Azadeh Kheirolomoom, Aris J. Kare, Elizabeth S. Ingham, Ramasamy Paulmurugan, Elise R. Robinson, Mo Baikoghli, Mohammed Inayathullah, Jai W. Seo, James Wang, Brett Z. Fite, Bo Wu, Spencer K. Tumble, Marina N. Raie, R. Holland Cheng, Lisa Nichols, Alexander D. Borowsky, Katherine W. Ferrara
Ex vivo T-cell engineering is effective but complex, costly, and difficult to scale. A method to transfect T cells directly in situ could simplify T-cell immunotherapy, but T-cell targeting may also trigger activation, depletion, cytokine release, and phenotypic changes that must be understood. In vitro: >80% of Jurkat cells expressed mCherry with 16% aCD3-LNPs; ~97% became CD69⁺; aCD3 coating caused T-cell depletion and CD3e internalization. - In vivo 24 h: aCD3-LNPs transfected ~2–4% of splenic T cells and.
Sérgio Scalzo, Anderson K. Santos, Heloisa A. S. Ferreira, Pedro A. Costa, Pedro H. D. M. Prazeres, Natalia J. A. Da Silva, Lays C. Guimarães, Mário De Morais E Silva, Marco T. R. Rodrigues Alves, Celso T. R. Viana, Itamar C. G. Jesus, Alice P. Rodrigues, Alexander Birbrair, Anderson O. Lobo, Freder
Cardiomyocytes are hard-to-transfect cells, and gene therapy for cardiovascular disease is limited by insufficient delivery to cardiac tissue, nucleic acid degradation, and safety concerns with viral vectors. A safe, effective non-viral platform for pDNA delivery to cardiomyocytes is needed. LNP4 was the top performer: ~1.3-fold higher GFP fluorescence than the second-best LNP8 and ~10-fold higher than the lowest performer LNP6. - LNP4 achieved >60% transfection efficiency at day 2 and >80% at day 4 in.
Yihua Pei, Yanjie Bao, Cristiano Sacchetti, Juthamart Brady, Kyra Gillard, Hailong Yu, Scott Roberts, Kumar Rajappan, Steven P. Tanis, Carlos G. Perez-Garcia, Padmanabh Chivukula, Priya P. Karmali
Systemic LNP delivery predominantly targets the liver, while extrahepatic delivery—especially to lung airway epithelium for diseases such as cystic fibrosis—remains challenging. DOTAP is a common cationic lipid for lung gene delivery but is racemic, pseudo-glyceryl, and slowly biodegradable. Novel readily hydrolysable DOTAP analogues are needed for safer and more effective inhaled/airway mRNA delivery. DOTAP+ and L1–L4 LNPs: <100 nm, >95% mRNA encapsulation, high mRNA purity; DOTAP− had ~71% encapsulation. - Freeze-thaw: all formulations retained size, PDI, and encapsulation within ~10% of initial values. -.
Drug carriers are as important as drugs themselves, but clinical translation of polymeric nanocarriers (PNCs) remains limited by incomplete understanding of how carrier architecture and physicochemical properties affect loading, circulation, targeting, and release. The review addresses this gap by systematically linking structural varieties of PNCs and their physicochemical properties to drug delivery profiles, and by highlighting. Representative quantitative findings highlighted in the review: - Aspect ratio and uptake: cylindrical particles with aspect ratio 3 were internalized about 4-fold faster than aspect ratio 1 particles in HeLa cells,.
Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O'neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F. Dipersio, Abdel Kareem Azab
T-cell-based immunotherapies such as CAR-T cells and bispecific T-cell engagers (BiTEs) have shown promise but have significant limitations: (1) poor pharmacokinetics requiring continuous infusion (BiTE half-life ~2 h), and (2) single-antigen targeting leading to antigen-loss tumor escape and relapse. A modular nanoparticle platform that addresses both limitations—extending half-life and enabling multispecific targeting—could improve efficacy. ### Nanoparticle Characterization & Pharmacokinetics | Parameter | Result | |---------------|------------| | Liposome size | ~100 nm | | Half-life (non-PEGylated nanoBiTE) | ~36 h | | Half-life (PEGylated nanoBiTE) |.
Hamideh Parhiz, Jacob S. Brenner, Et Al. (full Author List Not Included In The Supplied Excerpt)
T cells are notoriously resistant to exogenous mRNA transfection, limiting in vivo T cell engineering for immunotherapy, CAR T generation, and HIV cure. A safe, specific, and efficient in vivo mRNA delivery platform for CD4+ T cells was needed. In vitro: anti-CD4/mRNA-LNPs bound specifically to human CD4+ T cells; ~80% of CD3+CD8− splenocytes became ZsGreen1+ with anti-CD4/Cre mRNA-LNPs, even at the lowest dose. - In vivo biodistribution: spleen uptake was.
Johan Karlsson, Stephanie Y. Tzeng, Shayan Hemmati, Kathryn M. Luly, Olivia Choi, Yuan Rui, David R. Wilson, Kristen L. Kozielski, Alfredo Quiñones-Hinojosa, Jordan J. Green
Systemic delivery of RNA therapeutics with polymer-based nanocarriers is limited by poor colloidal stability in blood and inefficient intracellular delivery of siRNA to the cytosol. There is a need for nanoparticles that remain stable extracellularly but rapidly release RNA intracellularly. Crosslinking: Molecular weight increased by 42.1% (Mn) and 27.7% (Mw); acrylate peak intensity decreased by 79.1% ± 0.3%. - Serum stability: XbNPs retained siRNA encapsulation in 50% serum; non-crosslinked formulations.
Raza F, Zafar H, Zhang S, Kamal Z, Su J, Yuan W-E, Qiu M.
Cancer immunotherapy is limited by the immunosuppressive tumor microenvironment, patient heterogeneity, poor delivery of immunotherapeutics, and systemic immunotoxicity. Cell membrane-derived biomimetic nanoparticles may improve delivery and biodistribution, enhance targeting and immune stimulation, and overcome barriers faced by conventional nanomedicine. RBCM-coated nanoparticles improved half-life by up to 50% versus PEGylated nanoparticles and were detected in blood circulation after 72 h. - A size-reducible RBCM biomimetic system combined with.
Mandana T. Manzari, Yosi Shamay, Hiroto Kiguchi, Neal Rosen, Maurizio Scaltriti, And Daniel A. Heller
Precision medicine has transformed cancer therapy by enabling molecular profiling and optimized drug design, but clinical translation of many precision therapeutics is hindered by pharmacological limitations, including toxicities and drug resistance. Drug delivery materials can modulate a drug’s pharmacokinetics, biodistribution, and toxicity without compromising its molecular target engagement, offering a route to improve the therapeutic index. Kinase inhibitor landscape: More than 50 small-molecule protein kinase inhibitors have been FDA-approved, with the majority developed as targeted cancer therapeutics. - Dose-limiting toxicity example: In a phase I trial.
Kelly R. Rhodes, Randall A. Meyer, Justin Wang, Stephany Y. Tzeng, Jordan J. Green
Regulatory T cell (Treg)-based therapeutics show promise for treating autoimmune diseases and preventing transplant rejection, but adoptive Treg transfer is expensive, complex, and difficult to implement. "Off-the-shelf" non-cellular alternatives that can induce endogenous Tregs in vivo are needed. Existing artificial antigen presenting cells (aAPCs) are typically used for ex vivo T cell expansion and have limited application for immune. ### Protein Conjugation & aAPC Characterization | Parameter | PLGA aAPC | PLGA/PBAE aAPC | Significance | |---------------|---------------|--------------------|------------------| | Anti-CD3 conjugation (1× dose) |.
Bispecific T-cell engager (BiTE) immunotherapy is a promising cancer treatment, but clinical application is limited by high production costs and short in vivo half-life of BiTE proteins. A gene delivery system that enables sustained in vivo expression of BiTE could overcome these limitations, but existing non-viral vectors have low in vivo transfection efficiency. Metal-organic frameworks (MOFs) have been explored for nucleic acid delivery but. ### MOF Characterization & DNA Loading | Parameter | Result | |---------------|------------| | MOF size (TEM) | ~300 nm length × ~100 nm width | | MOF size (DLS) | 187.8 nm | | Zeta potential (MOF) | +24.7 mV | | Zeta.
Bradley Vis, Rachel E. Hewitt, Tom P. Monie, Camilla Fairbairn, Suzanne D. Turner, Stephen D. Kinrade, Jonathan J. Powell
Ultrasmall silica nanoparticles (USSN, <10 nm diameter) were recently shown to stimulate T lymphocytes directly at relatively low exposure doses, but the underlying mechanisms and associated cell signaling were unknown. Understanding whether USSN directly engage the T cell receptor (TCR) complex or act through other pathways is critical for both safety assessment and therapeutic translation of these inexpensive, rapidly dissolving nanoparticles. ### USSN Activation of T Cells (CD69 Expression, 24 h) | Cell Type | Control (%) | USSN (800 μM) (%) | Fold Increase | |---------------|-----------------|-----------------------|------------------| | CD4⁺ T cells (n=23).
Rui Zhang, Rakan El-Mayta, Timothy Murdoch, Claude Warzecha, Margaret Billingsley, Sarah Shepherd, Ningqiang Gong, Lili Wang, James Wilson, Daeyeon Lee, Michael J. Mitchell
LNP delivery to liver versus spleen is difficult to predict from formulation parameters, and the role of helper phospholipids in biodistribution and protein adsorption is incompletely understood. This study probed how helper lipid identity (DOPE vs DSPC) affects LNP accumulation in liver/spleen and interactions with apolipoprotein E (ApoE). DSPC-containing LNPs accumulated more in spleen than DOPE-containing LNPs (P = 0.0027); DOPE-containing LNPs accumulated more in liver (P < 0.0001). - QCM-D: DOPE LNP 42 showed stronger ApoE interaction than DSPC LNP.
Small-sized lipid nanoparticles (LNPs) are attractive for tissue penetration but often lose potency because lipid components diffuse out and serum proteins adsorb onto poorly packed surfaces. The study asked how the hydrophobic scaffold structure of pH-sensitive cationic lipids affects small-LNP stability, lipid miscibility, endosomal escape, and siRNA delivery. CL15H6-LNPs with 3 mol% PEG-DMG induced clear gene silencing (IC₅₀ ≈ 20 nM siRNA), whereas CL15A6-LNPs failed; cellular uptake of CL15H6-LNPs was about 2-fold higher. - Replacing cholesterol with ESM produced smaller.
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.
Coralie M. Backlund, Christopher R. Hango, Lisa M. Minter, Gregory N. Tew
Intracellular protein and antibody delivery is limited by inefficient carriers, high toxicity, and a frequent requirement for serum-free conditions, especially in difficult-to-transfect cells such as immune cells, stem cells, and neurons. A simple noncovalent carrier that works in complete media and across diverse cell types is needed. Commercial carriers: Xfect delivered GFP to all five cell types only in serum-free media; neurons were most challenging. PULSin delivered to all except neurons in serum-free media. ProteoJuice achieved only ~20%.
Serkan Yaman, Harish Ramachandramoorthy, Gizem Oter, Daria Zhukova, Tam Nguyen, Manoj K. Sabnani, Jon A. Weidanz, Kytai T. Nguyen
Melanoma is an aggressive skin cancer with limited treatment efficacy due to non-specific drug targeting, severe side effects, and multidrug resistance. Current cell-based immunotherapies are costly, complex, and carry long-term autoimmune risks. There is a need for a targeted, biocompatible drug delivery system that selectively recognizes melanoma cells and provides sustained drug release. Physicochemical properties: T-MNPs (1:2) were 193 ± 56 nm, PDI 0.265, zeta −36 mV; stable in saline for 48 h. Drug loading 61%; sustained trametinib release over 28 days, slowest at highest membrane ratio (1:2). - TCR.
