Nature Communications2023ResearchNon-viral Gene Delivery
Yue Wang, Shi-Kun Zhou, Yan Wang, Zi-Dong Lu, Yue Zhang, Cong-Fei Xu, Jun Wang
PD-1/PD-L1 blockade therapy is successful but often yields poor benefits due to insufficient T-cell infiltration and low intratumoral concentrations of PD-1/PD-L1 inhibitors. While strategies exist to increase either T-cell recruitment or inhibitor delivery, none actively recruit T cells while achieving tumor-specific delivery of PD-L1 inhibitors to specifically eliminate inhibition of tumor-infiltrating T cells. A strategy that addresses both. ### Nanoparticle Characterization | Parameter | Value | |---------------|-----------| | Hydrodynamic diameter | 107.2 nm | | PDI | ~0.2 | | Zeta potential | +15.3 mV | | Stability in 10% FBS | ≥5 days (size/PDI stable).
Read the article →Acta Pharmaceutica Sinica B2022ReviewNon-viral Gene Delivery
Yingping Zeng, Sufen Li, Shufen Zhang, Li Wang, Hong Yuan, Fuqiang Hu
Cancer immunotherapy is limited by tumor heterogeneity, immune cell disability, immunosuppressive tumor microenvironment (TME), and systemic immune toxicity. Cell membrane-coated nanoparticles (CMCNs) offer a biomimetic delivery strategy that inherits source-cell functions—immune evasion, tumor targeting, and biological compatibility—to precisely deliver immunotherapeutic drugs and enhance anti-cancer immunity. --- - Cancer vaccine response rates: clinical patient response to cancer vaccines remains relatively low at 11–50%; ICB inhibitors show ~80% effective rate in lymphoma but only 10–30% in solid tumors. - Sipuleucel-T (Provenge) extends overall survival by 4.1 months in metastatic castration-resistant prostate cancer. - APMC vaccine (B16F10 cancer cell membrane-coated CpG/aluminum phosphate nanoparticles): increased DC maturation, enhanced cellular/humoral immunity, improved tumor prevention/treatment and longer mouse survival vs.
Read the article →Nature Communications2021ResearchNon-viral Gene Delivery
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.
Read the article →Immunotherapy* (Future Science Group)2020ReviewNon-viral Gene Delivery
Mona Yazdani, Mahmoud Reza Jaafari, Javad Verdi, Behrang Alani, Mahdi Noureddini, Ali Badiee
Melanoma is a poorly immunogenic and highly aggressive skin cancer with limited long-term survival for advanced disease. Dendritic cell (DC)-based vaccines are promising immunotherapies, but their efficacy relies on critical factors including DC maturation state and efficient antigen delivery. Nanoparticulate delivery systems can enhance antigen delivery to ex vivo-generated DCs, mediate DC maturation (adjuvanticity), and promote cytoplasmic antigen presentation through MHC class I—potentially leading to potent antigen-specific immune responses. This review addresses the need to consolidate and evaluate the role of different nanoparticulate delivery systems in ex vivo-generated DC-based vaccines against melanoma. --- - Fusogenic liposomes (FLs): TCL/FLs-pulsed DCs significantly inhibited tumor growth until 17 days post-inoculation; superior to TCL/CLs-pulsed DCs. - Cationic liposomes (Srinivas et al.): Lipid 5 (shikimoyl headgroup) indu
Read the article →Therapeutic Delivery* (Future Science Group) Year/Publication: Published online 4 December 20182018ReviewNon-viral Gene Delivery
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Endosomal escape remains a major roadblock for delivering biological therapeutics such as DNA, siRNA, and proteins. Polymeric nanoparticles can protect cargo and target cells, but they often remain trapped in endosomal/lysosomal compartments, where cargo is degraded. A better understanding of how nanoparticle composition controls endosomal escape is needed to design more effective delivery systems. --- - Hydrophobicity: 30% BMA was optimal for hemolysis at endosomal pH 6.2; higher BMA prevented efficient nanoparticle disassembly. 30% BMA also improved DNA transfection in RAW 264.7 and JAWSII cells. - Polymer architecture: Cross-linked and hyperbranched nanoparticles showed significantly higher hemolysis than linear counterparts; hyperbranched variants enhanced MHC class I antigen presentation. - Protonation rates: Odd-numbered aminoethylene repeats in N-substituted polyaspartamides improved mRNA transcription and endosomal escape; even-
Read the article →Biomaterials2017ResearchNon-viral Gene Delivery
Shi Gn, Zhang Cn, Xu R, Niu Jf, Song Hj, Zhang Xy, Wang Ww, Wang Ym, Li C, Wei Xq, Kong Dl
Whole tumor cell lysates (TCL) are a broad source of tumor antigens for cancer vaccines, but soluble TCL is unstable, poorly taken up by dendritic cells (DCs), and inefficient at inducing cytotoxic T lymphocyte (CTL) responses. A delivery system was needed to protect TCL antigens, target DCs, and enhance antigen presentation and antitumor immunity. Nanoparticle characterization: Man-CTS-TCL NPs were ~120 nm, spherical, with a zeta potential of ~ −12 mV. Protein release was elevated at pH 5.0 compared with pH 7.4. - DC uptake/maturation: Man-CTS-TCL NPs increased.
Read the article →Nature Nanotechnology2014ResearchNon-viral Gene Delivery
Tarek R. Fadel, Fiona A. Sharp, Nalini Vudattu, Ragy Ragheb, Justin Garyu, Dongin Kim, Enping Hong, Nan Li, Gary L. Haller, Lisa D. Pfefferle, Sune Justesen, Kevan C. Herold, Tarek M. Fahmy
Adoptive cell transfer of tumor-specific T cells is a promising cancer immunotherapy, but efficient and economical ex vivo expansion of T cells remains a bottleneck. Artificial antigen-presenting cells (aAPCs) with high surface area and modular design could overcome cost and scalability limits of dendritic cell–based expansion. Murine T-cell expansion: CNPs expanded OT-1 CD8⁺ T cells ~200-fold after 2 weeks—more than 2× DYNA-EXO and more than 4× TET-EXO. - Cytokine efficiency: Expansion comparable to clinical standards using 1,000-fold less.
Read the article →Bioconjugate Chemistry2014ResearchNon-viral Gene Delivery
Hauptmann N, Pion M, Wehner R, Muñoz-Fernández M-A, Schmitz M, Voit B, Appelhans D
Dendritic cell (DC)-based immunotherapy requires efficient delivery of antigens to immature DCs (iDCs) and maintenance of their immunostimulatory and migratory functions. Cationic PEI carriers are limited by dose-dependent toxicity and aggregation at endosomal pH, so a biocompatible, pH-responsive carrier is needed. Biocompatibility: 4 µM His₆-Gp160 and 20 µM Ni(II)-NTA-DG did not significantly reduce monocyte or iDC viability. Polyplex 1:4 at 4 µM peptide/16 µM polymer significantly reduced monocyte viability; iDC viability was.
Read the article →Cellular Immunology (Elsevier)2014ResearchNon-viral Gene Delivery
Mingshui Chen, Haichao Ouyang, Shangyong Zhou, Jieyu Li, Yunbin Ye
Agonistic anti-OX40 monoclonal antibody (mAb) can enhance anti-tumor immunity in preclinical models, but as monotherapy it showed only marginal activity and no objective clinical responses in a phase I trial. A delivery system that improves T cell access, multivalent OX40 engagement, and sustained release of anti-OX40 mAb could enhance cytotoxic T lymphocyte (CTL) responses for cancer immunotherapy. Nanoparticle properties: Size 86.0 ± 14.1 nm; zeta potential −12.8 ± 1.5 mV; encapsulation efficiency 65.8 ± 5.6%; loading ~25% (248 ± 16.3 µg mAb/mg polymer); sustained release ~55% over 20 days with no initial burst.
Read the article →European Journal of Pharmaceutics and Biopharmaceutics2013ResearchNon-viral Gene Delivery
A.L. Silva, R.A. Rosalia, A. Sazak, M.G. Carstens, F. Ossendorp, J. Oostendorp, W. Jiskoot
Overlapping synthetic long peptides (SLPs) are promising for therapeutic cancer vaccination, but Montanide-based formulations have limitations including non-biodegradability, local side effects, poorly controlled release, and limited scalability. PLGA nanoparticles (NPs) offer a biodegradable alternative, but efficient encapsulation of moderately hydrophobic SLPs with low burst release had not been achieved. Standard acidic inner phase: Encapsulation efficiency was very low (1–30%) and burst release was extremely high (>70%) upon resuspension in PBS or IMDM. - Critical role of inner phase pH: Alkaline inner aqueous phase.
Read the article →Journal of Controlled Release2010ResearchNon-viral Gene Delivery
Luis J. Cruz, Paul J. Tacken, Remco Fokkink, Ben Joosten, Martien Cohen Stuart, Fernando Albericio, Ruurd Torensma, Carl G. Figdor
Antibody-mediated targeting of vaccine components to dendritic cells (DCs) enhances vaccine efficacy, but linking multiple antigens and immune modulators to a single antibody is limited. Slow-release PLGA particles conjugated to DC-specific antibodies could overcome this by delivering large antigen payloads and enabling co-encapsulation of adjuvants. However, it was unknown whether nano- or micrometer-sized PLGA particles are better suited for. Particle characterization: MPs ~2 µm, NPs ~200 nm; PEG-lipid coating reduced zeta potential; antigen encapsulation 78–91%; antibody conjugation ~20–30 µg/mg PLGA. - Antigen degradation kinetics: Encapsulated antigen.
Read the article →Molecular Pharmaceutics2007ResearchNon-viral Gene Delivery
C. M. Solbrig, J. K. Saucier-Sawyer, V. Cody, W. M. Saltzman, D. J. Hanlon
Current antitumor vaccines are limited by the small number of defined tumor-associated antigens (TAAs) for most solid tumors and by poor delivery of soluble antigen to dendritic cells (DCs). Autologous whole-tumor lysates contain the full antigenic repertoire, but soluble lysates are unstable and poorly internalized. Biodegradable PLGA nanoparticles may protect antigens, improve DC uptake, and enhance cross-presentation to cytotoxic T cells. Encapsulation: Efficiency increased with PLGA molecular weight and decreased with initial protein loading. For OVA at 50 mg/mL loading: 15K = 27%, 45K = 22%, 80K = 55%, 105K = 99%. At 100 mg/mL loading, encapsulation.
Read the article →Advanced Drug Delivery Reviews2005ReviewNon-viral Gene Delivery
Ying Waeckerle-Men And Marcus Groettrup
Dendritic cell (DC)-based vaccines are limited by the short persistence of MHC class I/peptide complexes on the DC surface—often only a few hours—when soluble peptides are loaded exogenously. This short presentation limits CTL activation and vaccine efficacy. The authors investigated biodegradable PLGA microspheres (PLGA-MS) as an antigen delivery system to human monocyte-derived DC (hMoDC), aiming to prolong antigen presentation on both MHC. Uptake: Immature hMoDC took up 10–30 PLGA-MS per cell within 1–4 h; 61% of cells were FITC-MS positive by flow cytometry. - Direct vaccination: A single injection of 20 µg TT in PLGA-MS yielded antibody titers.
Read the article →Trends in Immunology2002ReviewNon-viral Gene Delivery
James Harris, Dirk Werling, Jayne C. Hope, Geraldine Taylor, Chris J. Howard
Caveolae and caveolin are cholesterol-rich membrane microdomains involved in endocytosis, cholesterol regulation, and signal transduction, but their presence and function in immune cells have been contentious. This review addresses the need to clarify the distribution and roles of caveolae/caveolin in mammalian immune cells, especially given emerging evidence that they mediate pathogen internalization by antigen-presenting cells and participate in immune-cell signaling. --- 1. Distribution is contentious and context-dependent: Caveolae/caveolin are commonly found in myeloid cells (macrophages, mast cells, dendritic cells, neutrophils) but not consistently in lymphoid cells. More recent evidence suggests they may be present in all immune cell types, with expression/distribution dependent on activation and/or maturation state. 2. Species and cell-type differences in caveolin localization: Human CD26+ and CD21+ peripheral blood lymphocytes
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