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.
CAR T cell therapy is FDA/EMA-approved for B cell malignancies and multiple myeloma, but manufacturing relies on viral vectors—associated with safety concerns, high cost, and production challenges—or electroporation, which can be highly cytotoxic. Nanosystems may offer a safer, cost-effective alternative, but T cells are difficult to transfect, so rational design of lipid- and polymer-based carriers is urgently needed. Si-PDMAEMA-pDNA achieved 46% transfection in Jurkat cells and 44% in primary human T cells; pDNA/PEI-based systems reached 51% in Jurkat and 60% in primary human T cells. - pIAE + anti-CD3 + PiggyBac transposon.
Joel G. Rurik, István Tombácz, Amir Yadegari, Pedro O. Méndez Fernández, Swapnil V. Shewale, Li Li, Toru Kimura, Ousamah Younoss Soliman, Tyler E. Papp, Ying K. Tam, Barbara L. Mui, Steven M. Albelda, Ellen Puré, Carl H. June, Haig Aghajanian, Drew Weissman, Hamideh Parhiz, Jonathan A. Epstein
Fibrosis affects millions of people with cardiac disease and contributes to heart failure. While adoptive transfer of CAR T cells targeting fibroblast activation protein (FAP) has shown promise in reducing cardiac fibrosis, conventional CAR T cells persist for months to years and could cause chronic off-target toxicity by continuously attacking fibroblasts throughout the body, impairing wound healing.[reference:0][reference:1] A method to. ### LNP Characterization & In Vitro CAR Expression | Parameter | Result | |---------------|------------| | LNP hydrodynamic diameter | ~80 nm[reference:49] | | Polydispersity index | 0.02-0.06[reference:50] | | mRNA.
Rasheid Smith, Emad I. Wafa, Sean M. Geary, Kareem Ebeid, Suhaila O. Alhaj-Suliman, Aliasger K. Salem
Cancer vaccines as monotherapies have displayed limited clinical success due to the immunosuppressive tumor microenvironment (TME). Nanoscale formulations can enhance vaccine efficacy by combating TME immunosuppression, but there is a need for novel adjuvant formulations that can be combined with therapeutic cancer vaccines to improve antitumor immune responses and survival. ### Nanoparticle Characterization & Uptake | Parameter | PMG3 | PMG4 | PMG5 | |---------------|----------|----------|----------| | Hydrodynamic diameter | 231.7 ± 2.4 nm | 172.4 ± 3.0 nm | ~170 nm | | Zeta potential |.
Sajid Iqbal, Alessandro Francisco Martins, Muhammad Sohail, Jingjing Zhao, Qi Deng, Muhan Li, Zhongxi Zhao
Polymeric gene delivery vectors require detailed physicochemical characterization to ensure reproducible formulation and efficient transfection. PBAE-447 is a promising biodegradable cationic polymer, but its simple nanoparticles can degrade or aggregate in aqueous/physiological conditions. This study characterizes PBAE-447 and evaluates PEGylation and lyophilization to improve stability and transfection. Polymer characterization: Mn 5,354; Mw 9,575; MP 4,934; PDI 1.7. Complete end-capping confirmed by ¹H NMR. - Solubility/buffering/swelling: PBAE-447 completely soluble at 10 µg/µL in NaAc; buffering capacity required.
mRNA therapeutics have fueled hope to combat incurable diseases, but insufficient understanding of mRNA instability, immunogenicity, and delivery has impeded progress. The review argues that mRNA-based drugs—especially after the COVID-19 vaccine success—can become powerful, versatile tools, and that mRNA optimization and delivery systems are the key bottlenecks to solve. COVID-19 mRNA vaccines: ~90% effectiveness for full vaccination, 80% for partial; BNT162b2 95% efficacy in phase III; mRNA-1273 94.1% efficacy; Omicron-neutralizing antibodies largely undetectable in most recipients,.
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.
Mingyuan Li, Yuan Li, Shiqin Li, Lin Jia, Haomeng Wang, Meng Li, Jie Deng, Ali Zhu, Liqiao Ma, Weihong Li, Peng Yu, And Tao Zhu
The COVID-19 pandemic has greatly accelerated the application of mRNA technology, demonstrating its unique advantages over traditional biopharmaceutical and vaccine technology. However, mRNA instability in human physiological environments and inefficient in vivo delivery remain major barriers. mRNA chemical modifications and nano delivery systems are two key factors for in vivo applications. There is a need to summarize challenges for clinical. COVID-19 mRNA vaccine efficacy: BNT162b2 (Pfizer/BioNTech) 95% effective at 30 μg dose; mRNA-1273 (Moderna) 94.5% effective at 100 μg dose; both provide immunogenicity for at least 119 days after first vaccination. -.
Viral vectors dominate gene therapy but suffer from immunogenicity, insertional mutagenesis risk, cargo-size limits, and manufacturing challenges. Non-viral nanoparticles are safer, more economical, and easier to scale, but their clinical translation has been limited by inefficient delivery, especially for DNA and gene-editing cargoes that must reach the nucleus. There is a need to review non-viral nanomaterial design, delivery barriers, and. Viral vector dominance: Approximately 70% of gene therapy clinical trials to date have used viruses. - LNP gene editing in liver: A single administration of CRISPR-Cas9 LNPs achieved >97% reduction in target protein.
mRNA is a promising cancer immunotherapy platform for vaccines, cytokines, costimulatory receptors, and therapeutic antibodies, but it is unstable, immunogenic, and poorly delivered in vivo. Safer and more efficient delivery systems are needed to improve mRNA stability, cellular uptake, endosomal escape, and tumor-site accumulation. PL1 LNPs delivering CD137 or OX40 mRNA to tumor-infiltrating T cells, combined with anti-OX40 antibody, showed more significant antitumor activity than anti-OX40 antibody alone in multiple tumor models. -.
Therapeutic nucleic acids require safe and effective in vivo delivery vectors. Most gene and cell therapies rely on ex vivo gene delivery, which is laborious, time-consuming, and costly. PBAE is a promising biodegradable synthetic cationic polymer for in vivo gene delivery due to its transfection efficiency, biodegradability, and structural tunability. This review addresses the need for a systematic understanding of PBAE components and how. PBAE half-life: 1–7 h in aqueous conditions. - Freeze-thaw stability: PBAE NPs stored at −20 °C are stable through 8 freeze/thaw cycles without significant efficacy changes. - Optimal aqueous incubation: <10 min before.
Cancer immunotherapy — especially immune checkpoint inhibitors (ICIs), CAR-T cells, and oncolytic viruses (OVs) — has shown major clinical success but still faces low response rates, severe immune-related side effects, complex tumor microenvironment barriers, instability/short half-life of therapeutics, and high manufacturing costs. Polymeric systems are proposed as versatile carriers and immune-modulating platforms to improve targeting, safety. Representative findings highlighted in the review: - ICI delivery: Folate-PEI/PD-L1 siRNA blocked PD-1/PD-L1 interactions and reduced PEI cytotoxicity in ovarian cancer cells. PLGA-PEG nanoparticles targeted to CD8⁺ T.
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,.
Michael J. Mitchell, Margaret M. Billingsley, Rebecca M. Haley, Marissa E. Wechsler, Nicholas A. Peppas, Robert Langer
Nanoparticle (NP) research has generated promising preclinical results, but clinical translation remains limited. A major barrier is the mismatch between one-size-fits-all NP designs and the heterogeneous biological barriers across patients and diseases. Precision medicine offers patient stratification, but precision therapies still face delivery barriers. This review argues that intelligent NP design can overcome these barriers and improve both general and precision therapeutic outcomes. --- - Tumor accumulation: Meta-analysis of 232 datasets found that, on average, only 0.7% of injected NP doses reach tumors. - EPR effect variability: Up to 10–15% of injected NPs accumulate at tumor sites in some studies, compared with 0.1% of free drug; however, EPR is highly heterogeneous. - Targeted NP limitation: Antibody-targeted NPs interacted with only 2% of tumor cells in one study. - iCluster system: Inhibited tumor growth by up to 95% in viv
Qurrat Ul Ain, Estefania V.R. Campos, Ariel Huynh, Dominik Witzigmann, Sarah Hedtrich
Gene therapies are powerful tools to prevent, treat, and cure human diseases, but their application to skin diseases has received little attention despite the easy accessibility of skin and urgent medical need. The main obstacle is the unique barrier properties of human skin, which severely limit absorption of biomacromolecules and efficient delivery of nucleic acid payloads. This review discusses current approaches, successes, and failures of cutaneous gene therapy and provides guidance for next-generation concepts, with delivery strategies as the major translational obstacle. --- - Skin barrier: Human skin efficiently absorbs only small molecules (MW < ~800 Da) with moderate lipophilicity (logP 1–3), making biomacromolecule delivery challenging. - Clinical trial landscape: Of 1052 gene therapy trials, only 23 focus on skin conditions; ~70% of ongoing gene therapy trials are viral vector-based. - LNP optimization: Zwitterionic lipid ce
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.
siRNA therapeutics are limited by poor cellular uptake, serum nuclease degradation, and inefficient endosomal/lysosomal escape. Chitosan is biocompatible and biodegradable but has low transfection efficiency, largely due to poor buffering capacity and weak endosomal escape. Histidine grafting was explored to add imidazole groups (pKa ~6) that enhance proton-sponge buffering and siRNA delivery. Synthesis: FT-IR showed amide C=O at 1640 cm⁻¹ and N–H bending shift from 1590 to 1522 cm⁻¹; histidine O–H at 3016 cm⁻¹ disappeared. XRD showed loss of histidine crystal peaks at 18.8° and 24.3°, and HGCS polymers were.
Jiayu Zhou, Yishu Zhai, Jumei Xu, Tian Zhou, Lian Cen
PLGA microspheres are widely used for controlled drug release, but they often exhibit pronounced initial or mid-term burst release. A strategy is needed to finely tune drug release kinetics and suppress burst release, especially for water-soluble drugs. MSNs: Average size 119 nm; specific surface area 902.53 m²/g; pore volume 1.15 cm³/g; mean pore diameter 5.09 nm; maximum RB loading ~110 mg/g. - MSN-RB release: ~95% cumulative release within 56 h; Korsmeyer–Peppas n =.
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.
Rodgers, T., Muzzio, N., Watson, C., & Romero, G. (2021).
Gene-editing tools are large plasmid constructs that cannot spontaneously enter mammalian cells, and viral vectors are limited by cargo size, immunogenicity, and manufacturing challenges. PBAE nanoparticles are promising nonviral carriers, but unmodified PEG-PDHA nanoparticles release encapsulated plasmid DNA too rapidly for efficient intracellular delivery of large gene-editing cargo such as piggyBac transposon. Encapsulation and release: Optimal polymer/plasmid molar ratio = 0.36. Unmodified PEG-PDHA NPs released essentially all PBCAG within 2 h. Layer-by-layer NPs showed no detectable release within 24 h but transfection was.
Nanomedicine translation is limited by non-scalable, batch-variable bulk NP formulation methods that often produce large, polydisperse particles. Microfluidics offers precise control over microscale mixing and nanoprecipitation, enabling more reproducible NPs with controlled size, size distribution, and loading. This review summarizes microfluidic advances for lipid-, polymer-, and inorganic-based NPs. Representative quantitative findings from reviewed literature: - SHM-produced LNPs: 60–90 nm vs ~180 nm by pipette mixing; >90% hepatic gene silencing; up to 7-fold increased mRNA potency. - Parallelized SHM: 72 mL/min;.
mRNA vaccines have progressed from a scepticism-inducing idea to clinical reality, with COVID-19 catalysing the fastest vaccine development in history. Remaining needs include optimizing mRNA design, intracellular delivery, and applications beyond SARS-CoV-2 prophylaxis. This review describes mRNA vaccine technologies, with emphasis on lipid nanoparticles and other non-viral delivery vehicles. BNT162b2: 95% overall efficacy in phase III (43,548 participants); real-world Israel data: 94% against symptomatic COVID-19, 87% against hospitalization, 92% against severe disease; 90–100% efficacy across subgroups. -.
Gong N, Sheppard Nc, Billingsley Mm, June Ch, Mitchell Mj.
T-cell-based immunotherapies have shown clinical success in B-cell malignancies, but broad implementation is limited by insufficient T-cell expansion, poor trafficking into solid tumours, T-cell exhaustion in hostile tumour microenvironments, and loss of target antigen expression. Nanomaterials may uniquely overcome these barriers through rational design. IL-2-Fc fusion-protein-modified liposomes delivered to the surface of >95% of adoptively transferred T cells, inducing enhanced T-cell proliferation in tumour-bearing mice. - IL-15 superagonist nanogel backpacked onto.
Adoptive T cell therapy has revolutionized treatment of some hematologic malignancies but remains limited in solid tumors—especially central nervous system (CNS) tumors—by poor intratumoral delivery across anatomical barriers, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction caused by immunosuppressive tumor microenvironments. Nanoparticles may overcome these limitations by improving ex vivo T cell manufacture. Representative findings from cited studies: - Nanostructured PEG hydrogels with anti-CD3-conjugated gold nanoparticles enabled T cell activation, proliferation, and memory. - Immunoliposomes targeting CD90 delivered a.
