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.
Cm Jogdeo, K Siddhanta, A Das, L Ding, S Panja, N Kumari, D Oupický
A review of polymer-based alternatives to lipid gene delivery, including polyplexes and polymer–nucleic acid conjugates, with attention to chemical tunability and clinical translation.
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.
Chemical Society Reviews* (as indicated by review format; exact volume/pages and DOI not included in the supplied file)2021ReviewNon-viral Gene Delivery
Yingshu Guo, Xiuping Cao, Xiaofei Zheng, Sk Jahir Abbas, Juan Li, Weihong Tan
Cancer treatment still relies heavily on chemotherapy, which causes severe damage to normal cells and systemic side effects. Safer, more selective drug delivery strategies are needed. Nanocarriers based on nucleic acids (NCNAs) are attractive because nucleic acids offer biocompatibility, low toxicity, programmable structures, controllable size, and modifiability—advantages that address limitations of cationic polymers, dendrimers, and inorganic nanoparticles. --- - DNA tetrahedron loaded with 5-fluorouracil: after 12 h co-incubation, the percentage of drug in cells was nearly 40%, demonstrating stable and efficient drug delivery. - DNA/RNA hybrid spherical nucleic acid with siRNA: rapidly absorbed by more than 60 kinds of cells; protected siRNA from enzymatic digestion and released it upon intracellular Dicer cleavage. - Se/Ru metal–organic nanoparticles + siRNA: enhanced cell uptake and promoted siRNA escape from endosomes/lysosomes, p
Gene therapy requires safe, precise, efficient, and cost-effective delivery. Viral vectors are efficient but face manufacturing, cost, and safety challenges; non-viral vectors are safer and more scalable but often have low delivery efficiency. Magnetic nanoparticles (MNPs) have emerged as a promising strategy to enhance viral and non-viral gene delivery under an external magnetic field, while also enabling magnetic targeting, MRI tracking, and magnetic hyperthermia. --- - Magnetofection speed: MNP-based gene carriers can be attracted to cell surfaces in a few minutes, compared with hours for regular transfection. - Transfection enhancement: EMF enhanced lipid/SPIO-mediated transfection sixfold. PEI/Si@MNP with Dox and P-gp shRNA showed magnetically targeted delivery under 0.42 T for 12 h. - In vivo neuronal transfection: NeuroMag delivered EYFP-channelrhodopsin to rat visual cortex neurons with 72.66% and 86.63% expression at 3 and 30 d
Schlich M, Palomba R, Costabile G, Mizrahy S, Pannuzzo M, Peer D, Decuzzi P
Endosomal escape remains the major intracellular barrier for RNA therapeutics. Only a small fraction of RNA delivered by ionizable lipid nanoparticles (LNPs) reaches the cytosol, where siRNA, miRNA, mRNA, and CRISPR components must act. A deeper mechanistic understanding is needed to design next-generation LNPs with improved cytosolic delivery. Only 1–2% of siRNA delivered by MC3-LNPs was visualized in the cytosol in one key study; another estimated ~3.5% cytosolic release. - Endosomal escape occurs in a narrow time window from a hybrid early/late endosome.
Gene therapy has enormous therapeutic potential, but clinical translation is limited by the delivery problem: nucleic acids are negatively charged, unstable, and must overcome multiple biological barriers to reach their intracellular site of action. Viral vectors are efficient but suffer from immunogenicity, limited cargo capacity, insertional mutagenesis risk, and manufacturing challenges. There is a need for innovative synthetic materials that. Ionizable lipid nanoparticles: The most effective formulations for siRNA delivery included lipids with three or more hydrophobic tails, secondary and tertiary amines, and a particle surface pKa of ~5.5–7.0, enabling.
Nucleic acids can be used to engineer the immune system, but their clinical use requires better specificity and intracellular delivery efficiency. Viral vectors have manufacturing, cargo-capacity, safety, and immunological drawbacks; therefore, polymers are being developed as non-viral delivery vehicles whose chemical and physical properties can be tuned to improve efficacy. No primary quantitative results are reported; the review summarizes qualitative outcomes from cited studies: - CDN/PBAE nanoparticles promoted APC uptake and significantly reduced tumor growth after intratumoral.
Liposomes are attractive pharmaceutical carriers because they encapsulate hydrophilic and hydrophobic drugs and are biocompatible and biodegradable. However, conventional liposomes suffer from aggregation/fusion, premature payload release, rapid clearance by the mononuclear phagocyte system (MPS), low entrapment efficiency for some drugs, poor target selectivity, and inefficient intracellular delivery. Design optimization is needed to improve. Remote loading achieved encapsulation efficiency up to 90%; cyclodextrin-based loading achieved drug-to-lipid ratios >1000-fold higher than passive loading. - Doxil, a PEGylated liposomal doxorubicin formulation.
Jayoung Kim, Adam C. Mirando, Aleksander S. Popel, Jordan J. Green
Angiogenesis is normally balanced by pro- and anti-angiogenic factors, but imbalance leads to aberrant angiogenesis in ischemia, tissue regeneration, cancer, and neovascular age-related macular degeneration (wet AMD). Gene therapy is a promising strategy to introduce exogenous nucleic acids that express or silence target agents, thereby engineering neovascularization in both directions. Non-viral gene delivery nanoparticles have been widely investigated, but clinical translation remains hampered by safety, delivery efficiency, and therapeutic effect. This review consolidates key targets, non-viral nanoparticle approaches, and preclinical/clinical applications for angiogenesis modulation. --- - Ischemic limb: PEI/heparin-pVEGF nanoparticles increased capillary density >3-fold in mouse ischemic limb. PBAE-pVEGF-transfected HUVECs achieved 50% limb salvage vs 30% for lipo-pVEGF and 12.5% for PEI-pVEGF. - Myocardial infarction: WSLP-deliver
Non-viral nucleic acid delivery requires carriers that protect DNA/RNA from nucleases and facilitate intracellular delivery. Solid lipid nanoparticles (SLNs) are promising, but the molecular mechanisms by which they assemble with nucleic acids, transfect cells, and release cargo remain poorly understood compared with cationic lipids and polymers. Empty SLNs are typically 50–200 nm; after nucleic acid addition, SLNplexes can reach up to about 500 nm. For general in vivo use, ≤120 nm is preferred. - Cationic SLN formulations usually show zeta potential > +30 mV,.
Amphiphilic poly(amino acid)-based micelles are attractive for systemic drug delivery because they are biodegradable, biocompatible, have functional side groups, can load diverse drugs, and can exploit the EPR effect. However, low cargo capacity and poor stability in blood remain major barriers to clinical translation. This review summarizes the chemistry, drug-loading forces, in vitro/in vivo challenges, and strategies to improve loading and. Drug loading examples: PEG-b-PAsp-DOX conjugate DL 17%, 15–60 nm; PEG-b-PGlu-CDDP coordination DL 30%, ~30–40 nm; NK105 PTX DL 23%, ~85 nm; PEG-b-PGlu CPT-11 conjugate DL 20%, 20 nm; mPEG-b-PGlu DOX electrostatic DL.
Li, Y.; Maciel, D.; Rodrigues, J.; Shi, X.; Tomás, H
Despite extensive research, therapeutic delivery still faces major barriers: poor plasma stability, rapid clearance by the reticuloendothelial system (RES), and intracellular obstacles such as endosomal entrapment and lysosomal degradation. Biodegradable polymer nanogels (NGs) — physically or chemically cross-linked, water-swollen, submicrometer hydrophilic polymer networks — are promising because they can encapsulate or conjugate drugs/nucleic. Chitosan/alginate NGs improved gene transfection in 293T cells 4-fold compared with CTS NGs without alginate. - Redox-sensitive HA NGs protected siRNA; 94% remained entrapped after 110 min without GSH, while at 10 mM.
Cancer gene therapy requires safe and efficient delivery of nucleic acids, but viral vectors carry risks of immunogenicity and insertional tumorigenicity, while non-viral polymeric vectors are safer but less efficient. The review addresses the need for targeted polymeric nanoparticles that achieve tumor-specific accumulation and cancer-specific transfection through passive targeting, active ligand targeting, and. Representative quantitative findings highlighted in the review: - Transferrin targeting: Tf-conjugated PEG-PEI nanoparticles transfected distant tumor cells in vivo 10–100 times greater than non-tumor cells following.
Therapeutic nucleic acids—including plasmid DNA, mRNA, siRNA, miRNA, antisense oligonucleotides, and aptamers—have broad therapeutic potential, but their delivery to the correct intracellular site of action remains the dominant bottleneck. Polyplexes, formed by electrostatic complexation of nucleic acids with cationic polymers, are a promising non-viral delivery strategy, but their rational design requires a detailed understanding of. First polymer-based human gene therapy study (1994): transferrin-polylysine/IL-2 pDNA polyplexes were used ex vivo to transfect patient melanoma cells as a vaccine. - Clinical scale: by 2012, more than 2000 clinical.
Paulina Wyrozumska, Justyna Meissner, Monika Toporkiewicz, Marta Szarawarska, Kazimierz Kuliczkowski, Maciej Ugorski, Marta A. Walasek & Aleksander F. Sikorski
Most cancer gene therapy research has focused on solid tumors, while blood cancers such as leukemia and lymphoma have received less attention. There is a need for a lipid carrier that protects antisense oligonucleotides or plasmid DNA from enzymatic degradation, is stable in serum, has low toxicity, and can efficiently deliver cargo to leukemia/lymphoma cells and inhibit tumor growth in vivo. L-cL size was 116.3 ± 7.8 nm; zeta potential 6.6 ± 0.9 mV. - Encapsulation efficiency for pDNA was 80–95%; pDNA content ~120 µg/ml. - Stable as a suspension for 12 months at 4°C; stable after freeze-drying for 3 months.
Fabienne Danhier, Eduardo Ansorena, Joana M. Silva, Regis Coco, Aude Le Breton, Véronique Préat
PLGA is one of the most successfully developed biodegradable polymers, with FDA and EMA approval for parenteral drug delivery, but a comprehensive overview linking its formulation methods, physicochemical pitfalls, targeting strategies, and applications across multiple diseases was needed. This review presents why PLGA has been chosen for nanoparticle-based drug delivery and how its properties can be exploited to target specific organs, tissues. Encapsulation efficiency and drug loading: EE varies widely from 6% (dexamethasone) to 90% (paclitaxel); mean EE around 60–70% for drugs such as estradiol or xanthones. However, drug loading is generally poor—around 1%.
The immune system can recognize and kill pre-cancer and cancer cells, but surviving tumor cells learn to escape immune surveillance after immunoselection. Cancer immunotherapy aims to overcome these escape mechanisms. Nanomedicine offers tools—nanodiagnostics and nanobiopharmaceuticals—to deliver antigens, adjuvants, cytokines, and nucleic acids, and to target immune cells or the tumor microenvironment, potentially improving the efficacy of cancer immunotherapy. --- - G3139-LNP (CpG ODN against Bcl-2 encapsulated in lipid nanoparticles): enhanced IFN-γ, IL-2, IL-4, and IL-10 by ~4-fold; significantly enlarged spleen; inhibited tumor growth by >50%; prolonged host survival by 245%. - IL-18 + liposomal doxorubicin combination: 22% of mice remained tumor-free for 6 months vs 0% for either monotherapy in an ID8 ovarian tumor model. - Sipuleucel-T (Provenge®): first FDA-approved cancer therapeutic vaccine (April 2010); in phase III, extended
Parhamifar, L.; Larsen, A. K.; Hunter, A. C.; Andresen, T. L.; Moghimi, S. M
Efficient transfection with low toxicity is essential for nucleic acid therapeutics, but synthetic polycations such as polyethylenimine (PEI) are limited by cytotoxicity. This review critically assesses the safety and efficacy challenges of PEI-based polyplexes, identifies deficiencies in the field, and proposes avenues for designing safer polycationic vectors for clinical gene therapy and RNA interference delivery. Branched 25 kDa PEI is among the most efficient polycationic transfectants but also among the most cytotoxic. - PEI polyplexes damage plasma membranes, causing phosphatidylserine redistribution and LDH leakage without.
Nanotechnology enables control and manufacture of structures in the nanometer range, and nanoparticles exhibit novel properties that differ from bulk materials. There is a need for targeted drug delivery systems that improve solubility, bioavailability, sustained release, protection from degradation, and site-specific delivery while reducing systemic toxicity—especially for cancer, vaccines, and oral protein therapeutics. 100 nm nanoparticles had 2.5-fold greater uptake than 1 µm microparticles and 6-fold greater uptake than 10 µm microparticles by Caco-2 cells. - DOX-dendrimer was >10 times less toxic than free DOX to colon carcinoma.
Non-viral nucleic acid delivery systems—lipoplexes, polyplexes, and lipopolyplexes—are limited mainly by poor endosomal escape. The review examines whether histidine- and imidazole-containing carriers can exploit the acidic endosomal environment to destabilize membranes and improve cytosolic delivery of DNA, mRNA, siRNA, and oligonucleotides. HpK transfection was 3–4.5 orders of magnitude higher than polylysine in HepG2; optimal with 63–100 histidyl residues (33–50%). - HpK delivered DNA but not 25-mer ODN; highly histidylated HoK delivered ODN but not DNA.
Systemic non-viral gene delivery is limited by rapid clearance, toxicity, and poor target-cell access. Cationic lipid–DNA lipoplexes are effective in vitro but perform poorly in vivo because they aggregate with serum proteins, are cleared by the reticuloendothelial system (RES), and accumulate mainly in lung and liver rather than target tissues. There is a need for stable, sub-100 nm lipid nanoparticles that encapsulate nucleic acids, circulate. Lipoplexes have a blood half-life of <5 min; less than 2% remain in circulation 10 min after injection, and most redistribute from lung to liver within 60 min. - PEG-shielded lipid NPs typically have circulation.
Polymer-based siRNA delivery is promising but faces limitations similar to polymer-based DNA delivery, yet the two nucleic acids differ fundamentally in size, stiffness, stability, site of action, and duration of effect. This review addresses the need to understand these distinctions so that knowledge from the longer-studied field of polymeric DNA delivery can be adapted rationally to siRNA delivery. Persistence length: dsDNA ~50 nm; dsRNA ~70 nm. RNA is stiffer; 21 bp siRNA behaves as a rigid rod and is unlikely to condense further, risking incomplete encapsulation or large complexes. - Size limit: Non-specific.
Mattias Hallbrink, Johannes Oehlke, Gisela Papsdorf, Michael Bienert
Cell-penetrating peptides (CPPs) efficiently translocate across plasma membranes and are promising delivery vectors for therapeutic macromolecules. However, the influence of cell state, density, and peptide-to-cell ratio on CPP uptake and degradation has received little attention. Understanding whether CPP uptake is governed by peptide concentration or by the peptide-to-cell ratio is critical for experimental design and reproducibility, as. ### Effect of Culture Age on MAP Uptake (1 μM, 1 h) | Culture Age | Control Cells (μM) | Energy-Depleted Cells (μM) | |-----------------|-----------------------|-------------------------------| | 2 days | 24 | 20 | | 4.
Polymeric nucleic acid drugs—plasmid DNA, antisense oligonucleotides, and ribozymes—require protection from nucleases and efficient intracellular delivery to cytoplasm/nucleus. Viral vectors are efficient but immunogenic and safety-limited; non-viral cationic lipid systems are promising, but the mechanism of endosomal escape and the specific role of phosphatidylethanolamine (PE) remain unclear. DNA condensation occurs near charge neutralization; maximum in vitro transfection is near \(+/- \approx 1\), but in vivo formulations often use \(+/- >3\) to prevent aggregation. - Unsaturated PE alone adopts hexagonal.
