bims-novged 2024-03-03 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2024‒03‒03
sixteen papers selected by
the Merkel lab, Ludwig-Maximilians University

Analytical techniques for the characterization of nanoparticles for mRNA delivery.
In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors.
High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models.
Cyclization-enhanced poly(β-amino ester)s vectors for efficient CRISPR gene editing therapy.
RNA interference in the era of nucleic acid therapeutics.
Charge neutralized poly(β-amino ester) polyplex nanoparticles for delivery of self-amplifying RNA.
Development of cationic solid lipid nanoparticles incorporating cholesteryl-9-carboxynonanoate (9CCN) for delivery of antagomiRs to macrophages.
Recent Advances in Intranasal Administration for Brain-Targeting Delivery: A Comprehensive Review of Lipid-Based Nanoparticles and Stimuli-Responsive Gel Formulations.
RNA-encapsulating lipid nanoparticles in cancer immunotherapy: From pre-clinical studies to clinical trials.
Nanocarrier-Mediated Drug Delivery via Inhalational Route for Lung Cancer Therapy: A Systematic and Updated Review.
Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture enhanced endocytosis.
Instability of membranes containing ionizable cationic lipids: Effects of the repulsive range of headgroups and tail structures.
Nanogel delivery systems for cationic peptides: More than a 'One Size Fits All' solution.
Effect of Different Karyophilic Peptides on Physical Characteristics and In Vitro Transfection Efficiency of Chitosan-Plasmid Nanoparticles as Nonviral Gene Delivery Systems.
Advanced lung organoids for respiratory system and pulmonary disease modeling.
Surface Functionalized Lipid Nanoparticles in Promoting Therapeutic Outcomes: An Insight View of the Dynamic Drug Delivery System.

Eur J Pharm Biopharm. 2024 Feb 22. pii: S0939-6411(24)00061-4. [Epub ahead of print] 114235

Analytical techniques for the characterization of nanoparticles for mRNA delivery.

Sara S Nogueira, Eleni Samaridou, Johanna Simon, Simon Frank, Moritz Beck-Broichsitter, Aditi Mehta.

  Nanotechnology-assisted RNA delivery has gotten a tremendous boost over the last decade and made a significant impact in the development of life-changing vaccines and therapeutics. With increasing numbers of emerging lipid- and polymer-based RNA nanoparticles progressing towards the clinic, it has become apparent that the safety and efficacy of these medications depend on the comprehensive understanding of their critical quality attributes (CQAs). However, despite the rapid advancements in the field, the identification and reliable quantification of CQAs remain a significant challenge. To support these efforts, this review aims to summarize the present knowledge on CQAs based on the regulatory guidelines and to provide insights into the available analytical characterization techniques for RNA-loaded nanoparticles. In this context, routine and emerging analytical techniques are categorized and discussed, focusing on the operation principle, strengths, and potential limitations. Furthermore, the importance of complementary and orthogonal techniques for the measurement of CQAs is discussed in order to ensure the quality and consistency of analytical methods used, and address potential technique-based differences.

Keywords:  Analytical characterization; Critical quality attributes; Lipid-based nanoparticles; Nanoparticles; Physico-chemical properties; Polymer-based nanoparticles; mRNA; mRNA delivery

DOI:  https://doi.org/10.1016/j.ejpb.2024.114235
Nat Commun. 2024 Feb 26. 15(1): 1762

In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors.

Xuexiang Han, Junchao Xu, Ying Xu, Mohamad-Gabriel Alameh, Lulu Xue, Ningqiang Gong, Rakan El-Mayta, Rohan Palanki, Claude C Warzecha, Gan Zhao, Andrew E Vaughan, James M Wilson, Drew Weissman, Michael J Mitchell.

The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

DOI: https://doi.org/10.1038/s41467-024-45537-z
Nat Commun. 2024 Feb 29. 15(1): 1884

High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models.

Lulu Xue, Alex G Hamilton, Gan Zhao, Zebin Xiao, Rakan El-Mayta, Xuexiang Han, Ningqiang Gong, Xinhong Xiong, Junchao Xu, Christian G Figueroa-Espada, Sarah J Shepherd, Alvin J Mukalel, Mohamad-Gabriel Alameh, Jiaxi Cui, Karin Wang, Andrew E Vaughan, Drew Weissman, Michael J Mitchell.

Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.

DOI: https://doi.org/10.1038/s41467-024-45422-9
J Control Release. 2024 Feb 22. pii: S0168-3659(24)00127-5. [Epub ahead of print]

Cyclization-enhanced poly(β-amino ester)s vectors for efficient CRISPR gene editing therapy.

Xianqing Wang, Yinghao Li, A Sigen, Jing Lyu, Xi Wang, Zhonglei He, Irene Lara-Sáez, Ming Li, Wenxin Wang.

  Among non-viral gene delivery vectors, poly(β-amino ester)s (PAEs) are one of the most versatile candidates because of their wide monomer availability, high polymer flexibility, and superior gene transfection performance both in vitro and in vivo. Over two decades, PAEs have evolved from linear to highly branched structures, significantly enhancing gene delivery efficacy. Building on the proven efficient sets of monomers in highly branched PAEs (HPAEs), this work introduced a new class of cyclic PAEs (CPAEs) constructed via an A2 + B4 + C2 cyclization synthesis strategy and identified their markedly improved gene transfection capabilities in gene delivery applications. Two sets of cyclic PAEs (CPAEs) with rings of different sizes and topologies were obtained. Their chemical structures were confirmed via two-dimensional nuclear magnetic resonance and the photoluminescence phenomena, and their DNA delivery behaviours were investigated and compared with the HPAE counterparts. In vitro assessments demonstrated that the CPAEs with a macrocyclic architecture (MCPAEs), significantly enhanced DNA intracellular uptake and facilitated efficient gene expression while maintaining perfect biocompatibility. The top-performance MCPAEs have been further employed to deliver a plasmid coding dual single guide RNA-guided CRISPR-Cas9 machinery to delete COL7A1 exon 80 containing the c.6527dupC mutation. In recessive dystrophic epidermolysis bullosa (RDEB) patient-derived epidermal keratinocytes, MCPAEs facilitated the CRISPR plasmid delivery and achieved efficient targeted gene editing in multiple colonies.

Keywords:  CRISPR; Cyclic architecture; Macro ring; Non-viral gene editing; Poly(β-amino ester)s

DOI:  https://doi.org/10.1016/j.jconrel.2024.02.032
Nat Biotechnol. 2024 Feb 26.

RNA interference in the era of nucleic acid therapeutics.

Vasant Jadhav, Akshay Vaishnaw, Kevin Fitzgerald, Martin A Maier.

Two decades of research on RNA interference (RNAi) have transformed a breakthrough discovery in biology into a robust platform for a new class of medicines that modulate mRNA expression. Here we provide an overview of the trajectory of small-interfering RNA (siRNA) drug development, including the first approval in 2018 of a liver-targeted siRNA interference (RNAi) therapeutic in lipid nanoparticles and subsequent approvals of five more RNAi drugs, which used metabolically stable siRNAs combined with N-acetylgalactosamine ligands for conjugate-based liver delivery. We also consider the remaining challenges in the field, such as delivery to muscle, brain and other extrahepatic organs. Today's RNAi therapeutics exhibit high specificity, potency and durability, and are transitioning from applications in rare diseases to widespread, chronic conditions.

DOI: https://doi.org/10.1038/s41587-023-02105-y
Nanoscale Adv. 2024 Feb 27. 6(5): 1409-1422

Charge neutralized poly(β-amino ester) polyplex nanoparticles for delivery of self-amplifying RNA.

Nazgol Karimi Dastgerdi, Nurcan Gumus, Hulya Bayraktutan, Darryl Jackson, Krunal Polra, Paul F McKay, Fatemeh Atyabi, Rassoul Dinarvand, Robin J Shattock, Luisa Martinez-Pomares, Pratik Gurnani, Cameron Alexander.

Therapeutic self-amplifying RNA (saRNA) is a promising approach for disease treatment, as it can be administered in lower doses than messenger RNA (mRNA) to achieve comparable protein production levels. However, saRNA requires an appropriate delivery vehicle to protect it during transit and facilitate its transfection. A widely-adopted approach has been to use polycations to condense these large anionic macromolecules into polyplex nanoparticles, however their high charge density often elicits cytotoxic effects. In this study we postulated that we could improve the potency and tolerability of such delivery vehicles by co-formulating poly(β-amino ester)s saRNA polyplexes with a non-toxic anionic polymer, γ-polyglutamic acid (γ-PGA) to neutralize partially this positive charge. Accordingly, we prepared a poly(β-amino ester) from 1,6-hexanedioldiacrylate (HDDA) and 4-aminobutanol (ABOL) and initially evaluated the physicochemical properties of the binary polyplexes (i.e. formed from polymer and saRNA only). Optimised binary polyplex formulations were then taken forward for preparation of ternary complexes containing pHDDA-ABOL, saRNA and γ-PGA. Our findings demonstrate that γ-PGA integration into polyplexes significantly enhanced transfection efficacy in HEK293T and A431 cells without affecting polyplex size. Notably, γ-PGA incorporation leads to a pronounced reduction in zeta potential, which reduced the toxicity of the ternary complexes in moDC, NIH3T3, and A431 cells. Furthermore, the presence of γ-PGA contributed to colloidal stability, reducing aggregation of the ternary complexes, as evidenced by insignificant changes in polydispersity index (PDI) after freeze-thaw cycles. Overall, these results suggest that incorporating the appropriate ratio of a polyanion such as γ-PGA with polycations in RNA delivery formulations is a promising way to improve the in vitro delivery of saRNA.

DOI: https://doi.org/10.1039/d3na00794d
Eur J Pharm Biopharm. 2024 Feb 26. pii: S0939-6411(24)00064-X. [Epub ahead of print] 114238

Development of cationic solid lipid nanoparticles incorporating cholesteryl-9-carboxynonanoate (9CCN) for delivery of antagomiRs to macrophages.

Adrian Mallén, David A Narváez-Narváez, M D Pujol, Estanis Navarro, Josep Maria Suñé-Negre, Encarna García-Montoya, Pilar Pérez-Lozano, Benjamín Torrejón-Escribano, Marc Suñé-Pou, Miguel Hueso.

  Lipid-based nanoparticles are a useful tool for nucleic acids delivery and have been regarded as a promising approach for diverse diseases. However, off-targets effects are a matter of concern and some strategies to improve selectivity of solid lipid nanoparticles (SLNs) were reported. The goal of this study was to test formulations of SLNs incorporating lipid cholesteryl-9-carboxynonanoate (9CCN) as "eat-me" signal to target antagomiR oligonucleotides to macrophages. We formulate four SLNs, and those with a mean diameter of 200 nm and a Z-potential values between 25 and 40 mV, which allowed the antagomiR binding, were selected for in vitro studies. Cell viability, transfection efficiency and cellular uptake assays were performed within in vitro macrophages using flow cytometry and confocal imaging and the SLNs incorporating 25 mg of 9CCN proved to be the best formulation. Subsequently, we used a labeled antagomiR to study tissue distribution in in-vivo ApoE-/- model of atherosclerosis. Using the ApoE-/- model we demonstrated that SLNs with phagocytic signal 9-CCN target macrophages and release the antagomiR cargo in a selective way.

Keywords:  AntagomiR-125b; Cholesteryl-9-carboxynonanoate (9CCN); Macrophage transfection; Nucleic acid delivery; Solid lipid nanoparticles (SLNs); miR-125b

DOI:  https://doi.org/10.1016/j.ejpb.2024.114238
Int J Nanomedicine. 2024 ;19 1767-1807

Recent Advances in Intranasal Administration for Brain-Targeting Delivery: A Comprehensive Review of Lipid-Based Nanoparticles and Stimuli-Responsive Gel Formulations.

Jain Koo, Chaemin Lim, Kyung Taek Oh.

  Addressing disorders related to the central nervous system (CNS) remains a complex challenge because of the presence of the blood-brain barrier (BBB), which restricts the entry of external substances into the brain tissue. Consequently, finding ways to overcome the limited therapeutic effect imposed by the BBB has become a central goal in advancing delivery systems targeted to the brain. In this context, the intranasal route has emerged as a promising solution for delivering treatments directly from the nose to the brain through the olfactory and trigeminal nerve pathways and thus, bypassing the BBB. The use of lipid-based nanoparticles, including nano/microemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, has shown promise in enhancing the efficiency of nose-to-brain delivery. These nanoparticles facilitate drug absorption from the nasal membrane. Additionally, the in situ gel (ISG) system has gained attention owing to its ability to extend the retention time of administered formulations within the nasal cavity. When combined with lipid-based nanoparticles, the ISG system creates a synergistic effect, further enhancing the overall effectiveness of brain-targeted delivery strategies. This comprehensive review provides a thorough investigation of intranasal administration. It delves into the strengths and limitations of this specific delivery route by considering the anatomical complexities and influential factors that play a role during dosing. Furthermore, this study introduces strategic approaches for incorporating nanoparticles and ISG delivery within the framework of intranasal applications. Finally, the review provides recent information on approved products and the clinical trial status of products related to intranasal administration, along with the inclusion of quality-by-design-related insights.

Keywords:  bypassing BBB; in situ gel; lipid based nanoparticle; nose to brain delivery system

DOI:  https://doi.org/10.2147/IJN.S439181
Eur J Pharm Biopharm. 2024 Feb 22. pii: S0939-6411(24)00060-2. [Epub ahead of print] 114234

RNA-encapsulating lipid nanoparticles in cancer immunotherapy: From pre-clinical studies to clinical trials.

Tiffaney Hsia, Yunching Chen.

Nanoparticle-based delivery systems such as RNA-encapsulating lipid nanoparticles (RNA LNPs) have dramatically advanced in function and capacity over the last few decades. RNA LNPs boast of a diverse array of external and core configurations that enhance targeted delivery and prolong circulatory retention, advancing therapeutic outcomes. Particularly within the realm of cancer immunotherapies, RNA LNPs are increasingly gaining prominence. Pre-clinical in vitro and in vivo studies have laid a robust foundation for new and ongoing clinical trials that are actively enrolling patients for RNA LNP cancer immunotherapy. This review explores RNA LNPs, starting from their core composition to their external membrane formulation, set against a backdrop of recent clinical breakthroughs. We further elucidate the LNP delivery avenues, broach the prevailing challenges, and contemplate the future perspectives of RNA LNP-mediated immunotherapy.

DOI: https://doi.org/10.1016/j.ejpb.2024.114234
AAPS PharmSciTech. 2024 Feb 29. 25(3): 47

Nanocarrier-Mediated Drug Delivery via Inhalational Route for Lung Cancer Therapy: A Systematic and Updated Review.

Nargis Ara, Abdul Hafeez.

  Lung cancer is one of the most severe lethal malignancies, with approximately 1.6 million deaths every year. Lung cancer can be broadly categorised into small and non-small-cell lung cancer. The traditional chemotherapy is nonspecific, destroys healthy cells and produces systemic toxicity; targeted inhalation drug delivery in conjunction with nanoformulations has piqued interest as an approach for improving chemotherapeutic drug activity in the treatment of lung cancer. Our aim is to discuss the impact of polymer and lipid-based nanocarriers (polymeric nanoparticles, liposomes, niosomes, nanostructured lipid carriers, etc.) to treat lung cancer via the inhalational route of drug administration. This review also highlights the clinical studies, patent reports and latest investigations related to lung cancer treatment through the pulmonary route. In accordance with the PRISMA guideline, a systematic literature search was carried out for published works between 2005 and 2023. The keywords used were lung cancer, pulmonary delivery, inhalational drug delivery, liposomes in lung cancer, nanotechnology in lung cancer, etc. Several articles were searched, screened, reviewed and included. The analysis demonstrated the potential of polymer and lipid-based nanocarriers to improve the entrapment of drugs, sustained release, enhanced permeability, targeted drug delivery and retention impact in lung tissues. Patents and clinical observations further strengthen the translational potential of these carrier systems for human use in lung cancer. This systematic review demonstrated the potential of pulmonary (inhalational) drug delivery approaches based on nanocarriers for lung cancer therapy.

Keywords:  lung cancer; nanostructured lipid carriers; polymeric nanoparticles; pulmonary drug delivery; targeted drug delivery

DOI:  https://doi.org/10.1208/s12249-024-02758-1
bioRxiv. 2024 Feb 16. pii: 2024.02.15.580508. [Epub ahead of print]

Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture enhanced endocytosis.

Zhi-Jian He, Baiqiang Huang, Li-Heng Cai.

Pulmonary drug delivery is critical to the treatment of respiratory diseases. However, the human airway surface presents multiscale barriers to efficient drug delivery. Here we report a bottlebrush polyethylene glycol (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by the molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1,000) low molecular weight (∼1000 g/mol) PEG chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a novel carrier for pulmonary and mucosal drug delivery.Table of Contents:

DOI: https://doi.org/10.1101/2024.02.15.580508
Colloids Surf B Biointerfaces. 2024 Feb 20. pii: S0927-7765(24)00065-1. [Epub ahead of print]236 113807

Instability of membranes containing ionizable cationic lipids: Effects of the repulsive range of headgroups and tail structures.

Hao-Chun Huang, Chih-Jung Lin, Yu-Jane Sheng, Heng-Kwong Tsao.

  The stability of membranes formed by ionizable cationic lipids, which constitute the primary components in lipid nanoparticles capable of endosomal escape, is explored using coarse-grained dissipative particle dynamics. Three types of ionizable model lipids with different tail structures are considered. Endosome acidification causes the ionization of lipids, leading to an increased repulsive range between their headgroups. When electrostatic repulsion is modeled as a conservative force with a long-range cutoff distance (rc,HH), the membrane and vesicle experience a loss of structural integrity and develop holes as rc,HH is beyond a critical value, which varies with the tail structure. When Coulombic repulsion is explicitly incorporated and intensified, a fully ionized lipid membrane undergoes a loss of structural integrity, displaying a qualitative similarity to the effect observed with the increase in rc,HH on the membrane stability. Qualitatively similar results are obtained for partially ionized membranes as the fraction of charged lipids increases. The stability of a mixed lipid membrane containing both ionizable and conventional lipids is also investigated. The disruption of the bilayer structure occurs for a sufficiently high charged fraction. The membrane instability can be attributed to the decrease in the packing parameter, which significantly deviates from unity as the interaction range increases.

Keywords:  Bilayered membrane; Ionizable cationic lipid; Lipid nanoparticle; Long-range electrostatic force

DOI:  https://doi.org/10.1016/j.colsurfb.2024.113807
J Colloid Interface Sci. 2024 Feb 13. pii: S0021-9797(24)00345-X. [Epub ahead of print]663 449-457

Nanogel delivery systems for cationic peptides: More than a 'One Size Fits All' solution.

Sylvia N Kłodzińska, Qiuyu Wang, Natalia Molchanova, Najet Mahmoudi, Jijo J Vallooran, Paul R Hansen, Håvard Jenssen, Hanne Mørck Nielsen.

  Self-assembled hyaluronic acid-based nanogels are versatile drug carriers due to their biodegradable nature and gentle preparation conditions, making them particularly interesting for delivery of peptide therapeutics. This study aims to elucidate the relation between peptide structure and encapsulation in a nanogel. Key peptide properties that affect encapsulation in octenyl succinic anhydride-modified hyaluronic acid nanogels were identified as we explored the effect on nanogel characteristics using 12 peptides with varying charge and hydrophobicity. The size and surface properties of the microfluidics-assembled peptide-loaded nanogels were evaluated using dynamic light scattering, laser Doppler electrophoresis, and small angle neutron scattering. Additionally, the change in peptide secondary structure upon encapsulation in nanogels, their release from the nanogels, and the in vitro antimicrobial activity were assessed. In conclusion, the more hydrophobic peptides showed stronger binding to the nanogel carrier and localized internally rather than on the surface of the nanogel, resulting in more spherical nanogels with smoother surfaces and slower release profiles. In contrast, cationic and hydrophilic peptides localized at the nanogel surface resulting in fluffier nanogel structures and quick and more complete release in biorelevant medium. These findings emphasize that the advantages of nanogel delivery systems for different applications depend on the therapeutic peptide properties.

Keywords:  Biopolymer; Cationic peptides; Drug delivery; Formulation; Nanogel; Self-assembly; Structure

DOI:  https://doi.org/10.1016/j.jcis.2024.02.101
Mol Biotechnol. 2024 Feb 24.

Effect of Different Karyophilic Peptides on Physical Characteristics and In Vitro Transfection Efficiency of Chitosan-Plasmid Nanoparticles as Nonviral Gene Delivery Systems.

María Eugenia Aranda-Barradas, Héctor Eduardo Coronado-Contreras, Yareli Lizbeth Aguilar-Castañeda, Karen Donají Olivo-Escalante, Francisco Rodolfo González-Díaz, Carlos Gerardo García-Tovar, Samuel Álvarez-Almazán, Susana Patricia Miranda-Castro, Alicia Del Real-López, Abraham Méndez-Albores.

  A strategy to increase the transfection efficiency of chitosan-based nanoparticles for gene therapy is by adding nuclear localization signals through karyophilic peptides. Here, the effect of the length and sequence of these peptides and their interaction with different plasmids on the physical characteristics and biological functionality of nanoparticles is reported. The karyophilic peptides (P1 or P2) were used to assemble nanoparticles by complex coacervation with pEGFP-N1, pQBI25 or pSelect-Zeo-HSV1-tk plasmids, and chitosan. Size, polydispersity index, zeta potential, and morphology, as well as in vitro nucleus internalization and transfection capability of nanoparticles were determined. The P2 nanoparticles resulted smaller compared to the ones without peptides or P1 for the three plasmids. In general, the addition of either P1 or P2 did not have a significant impact on the polydispersity index and the zeta potential. P1 and P2 nanoparticles were localized in the nucleus after 30 min of exposure to HeLa cells. Nevertheless, the presence of P2 in pEGFP-N1 and pQBI25 nanoparticles raised their capability to transfect and express the green fluorescent protein. Thus, karyophilic peptides are an efficient tool for the optimization of nonviral vectors for gene delivery; however, the sequence and length of peptides have an impact on characteristics and functionality of nanoparticles.

Keywords:  Chitosan; Gene therapy; Karyophilic peptides; Nanoparticles; Nuclear localization signal

DOI:  https://doi.org/10.1007/s12033-024-01087-9
J Tissue Eng. 2024 Jan-Dec;15:15 20417314241232502

Advanced lung organoids for respiratory system and pulmonary disease modeling.

Hyebin Joo, Sungjin Min, Seung-Woo Cho.

  Amidst the recent coronavirus disease 2019 (COVID-19) pandemic, respiratory system research has made remarkable progress, particularly focusing on infectious diseases. Lung organoid, a miniaturized structure recapitulating lung tissue, has gained global attention because of its advantages over other conventional models such as two-dimensional (2D) cell models and animal models. Nevertheless, lung organoids still face limitations concerning heterogeneity, complexity, and maturity compared to the native lung tissue. To address these limitations, researchers have employed co-culture methods with various cell types including endothelial cells, mesenchymal cells, and immune cells, and incorporated bioengineering platforms such as air-liquid interfaces, microfluidic chips, and functional hydrogels. These advancements have facilitated applications of lung organoids to studies of pulmonary diseases, providing insights into disease mechanisms and potential treatments. This review introduces recent progress in the production methods of lung organoids, strategies for improving maturity, functionality, and complexity of organoids, and their application in disease modeling, including respiratory infection and pulmonary fibrosis.

Keywords:  Lung organoid; bioengineeing platform; cellular niches; pulmonary fibrosis; respiratory infection

DOI:  https://doi.org/10.1177/20417314241232502
Curr Drug Targets. 2024 Feb 22.

Surface Functionalized Lipid Nanoparticles in Promoting Therapeutic Outcomes: An Insight View of the Dynamic Drug Delivery System.

Namish Manchanda, Harish Vishkarma, Muskan Goyal, Saurabh Shah, Paras Famta, Sushama Talegaonkar, Saurabh Srivastava.

  Compared to the conventional approach, nanoparticles (NPs) facilitate a non-hazardous, non-toxic, non-interactive, and biocompatible system, rendering them incredibly promising for improving drug delivery to target cells. When that comes to accomplishing specific therapeutic agents like drugs, peptides, nucleotides, etc., lipidic nanoparticulate systems have emerged as even more robust. They have asserted impressive ability in bypassing physiological and cellular barriers, evading lysosomal capture and the proton sponge effect, optimizing bioavailability, and compliance, lowering doses, and boosting therapeutic efficacy. However, the lack of selectivity at the cellular level hinders its ability to accomplish its potential to the fullest. The inclusion of surface functionalization to the lipidic NPs might certainly assist them in adapting to the basic biological demands of a specific pathological condition. Several ligands, including peptides, enzymes, polymers, saccharides, antibodies, etc., can be functionalized onto the surface of lipidic NPs to achieve cellular selectivity and avoid bioactivity challenges. This review provides a comprehensive outline for functionalizing lipid-based NPs systems in prominence over target selectivity. Emphasis has been put upon the strategies for reinforcing the therapeutic performance of lipidic nano carriers' using a variety of ligands alongside instances of relevant commercial formulations.

Keywords:  PEGylation.; Surface functionalization; ligands; lipid nanoparticles; targeted delivery; theranostics

DOI:  https://doi.org/10.2174/0113894501285598240216065627