bims-novged 2023-11-19 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2023–11–19
twelve papers selected by
the Merkel lab, Ludwig-Maximilians University

Zwitterionic Polymer-Decorated Lipid Nanoparticles for mRNA Delivery in Mammalian Cells.
Evaluation of the effects of storage conditions on spray-dried siRNA-LNPs before and after subsequent drying.
Impact of Peptide Sequence on Functional siRNA Delivery and Gene Knockdown with Cyclic Amphipathic Peptide Delivery Agents.
Efficient and Targeted siRNA Delivery to M2 Macrophages by Smart Polymer Blends for M1 Macrophage Repolarization as a Promising Strategy for Future Cancer Treatment.
Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease.
Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.
Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions.
Cationic Starch Nanoparticles for Enhancing CpG Oligodeoxynucleotide-Mediated Antitumor Immunity.
Synergetic regulation of cancer cells and exhausted T cells to fight cold tumors with a fluorinated EGCG-based nanocomplex.
Surface functionalization affects the retention and bio-distribution of orally administered mesoporous silica nanoparticles in a colitis mouse model.
Frontiers in nonviral delivery of small molecule and genetic drugs, driven by polymer chemistry and machine learning for materials informatics.
Simply and Cheaply Prepared Liposomal Membrane for Nanocarriers: High Encapsulation Efficiency Based on Broad Regulation of Surface Charges and pH-Switchable Performance.

Biomacromolecules. 2023 Nov 13.

Zwitterionic Polymer-Decorated Lipid Nanoparticles for mRNA Delivery in Mammalian Cells.

Phim-On Khunsuk, Chitsuda Pongma, Tanapat Palaga, Voravee P Hoven.

Lipid nanoparticles (LNPs) play a key role in the effective transport of mRNA into cells for protein translation. Despite the stealthiness of poly(ethylene glycol) (PEG) that helps protect LNPs from protein absorption and blood clearance, the generation of anti-PEG antibodies resulting in PEG allergies remains a challenge for the development of an mRNA vaccine. Herein, a non-PEG lipid was developed by conjugating 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) with an antifouling zwitterionic polymer, poly(2-methyacryloyloxyethyl phosphorylcholine) (PMPC), of different chain lengths. The PMPC-LNPs formulated from DPPE-PMPC were spherical (diameter ≈ 144-255 nm), neutral in charge, and stable at 4 °C for up to 28 days. Their fraction of stealthiness being close to 1 emphasized the antifouling characteristics of PMPC decorated on LNPs. The PMPC-LNPs were nontoxic to HEK293T cells, did not induce inflammatory responses in THP-1 cells, and exhibited an mRNA transfection efficiency superior to that of PEG-LNPs. This work demonstrated the potential of the developed zwitterionic polymer-conjugated LNPs as promising mRNA carriers.

DOI: https://doi.org/10.1021/acs.biomac.3c00649
Eur J Pharm Biopharm. 2023 Nov 11. pii: S0939-6411(23)00296-5. [Epub ahead of print]

Evaluation of the effects of storage conditions on spray-dried siRNA-LNPs before and after subsequent drying.

Christoph M Zimmermann, Leonie Deßloch, David C Jürgens, Paola Luciani, Olivia M Merkel.

  In an ideal world, pharmaceutical drugs would have infinite shelf life, no susceptibility to degradation, chemical reactions or loss of efficacy. In reality, these processes occur, however, making it desirable to extend a drugs' shelf life. Nucleic acid-based drugs are most commonly stored as aqueous suspension where they are vulnerable to microbial growth and degradation processes. Drying procedures, such as lyophilization and spray drying, help to reduce the products' residual moisture while increasing the products' shelf life and stability. The present study was designed to evaluate 90 days of storage of spray-dried siRNA-lipid nanoparticles (LNPs) at 4 °C and 25 °C. An updated Onpattro® composition modified with a positively charged helper lipid was used as the LNP carrier system. In an attempt to further reduce the residual moisture of our previously reported formulations, all LNP samples were subjected to a secondary drying step in the spray drying tower for 20 min. The measurement of physicochemical properties of spray-dried and subsequently dried LNPs resulted in sizes of 180 nm, PDI values of 0.1-0.15 and zeta potentials of +3 mV. Spray drying resulted in residual moisture levels of 3.6 - 4% and was reduced by subsequent drying to 2.8 - 3.1%. Aerodynamic properties after storage showed discrepancies depending on the storage conditions. MMADs remained at 2.8 µm when stored at 4 °C, whereas an increase to 5 µm at 25 °C was observed. Subsequent drying led to sizes of 3.6-3.8 µm, independent of the storage conditions. Spray-dried LNPs maintained bioactivity resulting in > 95% protein downregulation and confirming the lack of cytotoxic effects in a lung adenocarcinoma cell line. Furthermore, the spray-dried and subsequently dried LNPs stored for 3 months at 4 °C and 25 °C achieved up to 50% gene silencing of the house-keeping gene GAPDH after deposition on the mucus layer of Calu-3 cells. This study confirms the stability of spray-dried and subsequently dried LNPs over at least 90 days at 4 °C and 25 °C emphasizing the potential of dry powder inhalation of RNA-loaded LNPs as a therapy option for pulmonary diseases.

Keywords:  LNP; Onpattro®; RNA therapeutics; lipid nanoparticles; pulmonary delivery; shelf life; siRNA delivery; spray drying; storage; subsequent drying

DOI:  https://doi.org/10.1016/j.ejpb.2023.11.007
Mol Pharm. 2023 Nov 14.

Impact of Peptide Sequence on Functional siRNA Delivery and Gene Knockdown with Cyclic Amphipathic Peptide Delivery Agents.

Melissa L Jagrosse, Uday K Baliga, Christopher W Jones, Jade J Russell, Claudia I García, Rauf Ahmad Najar, Arshad Rahman, David A Dean, Bradley L Nilsson.

  Short-interfering RNA (siRNA) oligonucleotide therapeutics that modify gene expression by accessing RNA-interference (RNAi) pathways have great promise for the treatment of a range of disorders; however, their application in clinical settings has been limited by significant challenges in cellular delivery. Herein, we report a structure-function study using a series of modified cyclic amphipathic cell-penetrating peptides (CAPs) to determine the impact of peptide sequence on (1) siRNA-binding efficiency, (2) cellular delivery and knockdown efficiency, and (3) the endocytic uptake mechanism. Nine cyclic peptides of the general sequence Ac-C[XZ]4CG-NH2 in which X residues are hydrophobic/aromatic (Phe, Tyr, Trp, or Leu) and Z residues are charged/hydrophilic (Arg, Lys, Ser, or Glu) are assessed along with one acyclic peptide, Ac-(WR)4G-NH2. Cyclization is enforced by intramolecular disulfide bond formation between the flanking Cys residues. Binding analyses indicate that strong cationic character and the presence of aromatic residues that are competent to participate in CH-π interactions lead to CAP sequences that most effectively interact with siRNA. CAP-siRNA binding increases in the following order as a function of CAP hydrophobic/aromatic content: His < Phe < Tyr < Trp. Both cationic charge and disulfide-constrained cyclization of CAPs improve uptake of siRNA in vitro. Net neutral CAPs and an acyclic peptide demonstrate less-efficient siRNA translocation compared to the cyclic, cationic CAPs tested. All CAPs tested facilitated efficient siRNA target gene knockdown of at least 50% (as effective as a lipofectamine control), with the best CAPs enabling >80% knockdown. Significantly, gene knockdown efficiency does not strongly correlate with CAP-siRNA internalization efficiency but moderately correlates with CAP-siRNA-binding affinity. Finally, utilization of small-molecule inhibitors and targeted knockdown of essential endocytic pathway proteins indicate that most CAP-siRNA nanoparticles facilitate siRNA delivery through clathrin- and caveolin-mediated endocytosis. These results provide insight into the design principles for CAPs to facilitate siRNA delivery and the mechanisms by which these peptides translocate siRNA into cells. These studies also demonstrate the nature of the relationships between peptide-siRNA binding, cellular delivery of siRNA cargo, and functional gene knockdown. Strong correlations between these properties are not always observed, which illustrates the complexity in the design of optimal next-generation materials for oligonucleotide delivery.

Keywords:  cell-penetrating peptide; cyclic peptide; drug delivery; siRNA delivery

DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00455
ACS Biomater Sci Eng. 2023 Nov 18.

Efficient and Targeted siRNA Delivery to M2 Macrophages by Smart Polymer Blends for M1 Macrophage Repolarization as a Promising Strategy for Future Cancer Treatment.

David C Jürgens, Benjamin Winkeljann, Miriam Kolog Gulko, Yao Jin, Judith Möller, Joshua Winkeljann, Sahana Sheshachala, Alina Anger, Andreas Hörner, Nathan B P Adams, Nora Urbanetz, Olivia M Merkel.

  Cancer remains an issue on a global scale. It is estimated that nearly 10 million people succumbed to cancer worldwide in 2020. New treatment options are urgently needed. A promising approach is a conversion of tumor-promoting M2 tumor-associated macrophages (TAMs) as part of the tumor microenvironment to tumor-suppressive M1 TAMs by small interfering RNA (siRNA). In this work, we present a well-characterized polymeric nanocarrier system capable of targeting M2 TAMs by a ligand-receptor interaction. Therefore, we developed a blended PEI-based polymeric nanoparticle system conjugated with mannose, which is internalized after interaction with macrophage mannose receptors (MMRs), showing low cytotoxicity and negligible IL-6 activation. The PEI-PCL-PEI (5 kDa-5 kDa-5 kDa) and Man-PEG-PCL (2 kDa-2 kDa) blended siRNA delivery system was optimized for maximum targeting capability and efficient endosomal escape by evaluation of different polymer and N/P ratios. The nanoparticles were formulated by surface acoustic wave-assisted microfluidics, achieving a size of ∼80 nm and a zeta potential of approximately +10 mV. Special attention was given to the endosomal escape as the so-called bottleneck of RNA drug delivery. To estimate the endosomal escape capability of the nanocarrier system, we developed a prediction method by evaluating the particle stability via the inflection temperature. Our predictions were then verified in an in vitro setting by applying confocal microscopy. For cellular experiments, however, human THP-1 cells were polarized to M2 macrophages by cytokine treatment and validated through MMR expression. To show the efficiency of the nanoparticle system, GAPDH and IκBα knockdown was performed in the presence or absence of an MMR blocking excess of mannan. Cellular uptake, GAPDH knockdown, and NF-κB western blot confirmed efficient mannose targeting. Herein, we presented a well-characterized nanoparticle delivery system and a promising approach for targeting M2 macrophages by a mannose-MMR interaction.

Keywords:  M2 tumor-associated macrophages; macrophage mannose receptors; microfluidics; polymer blends; siRNA; surface acoustic waves

DOI:  https://doi.org/10.1021/acsbiomaterials.3c01595
Acta Biomater. 2023 Nov 09. pii: S1742-7061(23)00646-3. [Epub ahead of print]

Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease.

Xuan He, Zhimin Chang, Fangman Chen, Wensheng Zhang, Madi Sun, Tongfei Shi, Jie Liu, Peiyu Chen, Kunbao Zhang, Shan Guan, Zhibin Zhao, Mingqiang Li, Wen-Fei Dong, Dan Shao, Chao Yang.

  RNA interference (RNAi) presents great potential against intractable liver diseases. However, the establishment of specific, efficient, and safe delivery systems targeting hepatocytes remains a great challenge. Herein, we described a promising hepatocytes-targeting system through integrating triantennary N-acetylgalactosamine (GalNAc)-engineered cell membrane with biodegradable mesoporous silica nanoparticles, which efficiently and safely delivered siRNA to hepatocytes and silenced the target PCSK9 gene expression for the treatment of non-alcoholic fatty liver disease. Having optimized the GalNAc-engineering strategy, insertion orders, and cell membrane source, we obtained the best-performing GalNAc-formulations allowing strong hepatocyte-specific internalization with reduced Kupffer cell capture, resulting in robust gene silencing and less hepatotoxicity when compared with cationic lipid-based GalNAc-formulations. Consequently, a durable reduction of lipid accumulation and damage was achieved by systemic administering siRNAs targeting PCSK9 in high-fat diet-fed mice, accompanied by displaying desirable safety profiles. Taken together, this GalNAc-engineering biomimetics represented versatile, efficient, and safe carriers for the development of hepatocyte-specific gene therapeutics, and prevention of metabolic diseases. STATEMENT OF SIGNIFICANCE: Compared to MSN@LP-GN3 (MC3-LNP), MSN@CM-GN3 exhibited strong hepatocyte targeting and Kupffer cell escaping, as well as good biocompatibility for safe and efficient siRNA delivery. Furthermore, siPCSK9 delivered by MSN@CM-GN3 reduced both serum and liver LDL-C, TG, TC levels and lipid droplets in HFD-induced mice, resulting in better performance than MSN/siPCSK9@LP-GN3 in terms of lipid-lowering effect and safety profiles. These findings indicated promising advantages of our biomimetic GN3-based systems for hepatocyte-specific gene delivery in chronic liver diseases. Our work addressed the challenges associated with the lower targeting efficiency of cell membrane-mimetic drug delivery systems and the immunogenicity of traditional GalNAc delivery systems. In conclusion, this study provided an effective and versatile approach for efficient and safe gene editing using ligand-integrated biomimetic nanoplatforms.

Keywords:  GalNAc; PCSK9; biomimetic; cell membrane; hepatocyte-specific

DOI:  https://doi.org/10.1016/j.actbio.2023.10.038
Nat Commun. 2023 Nov 11. 14(1): 7322

Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.

Tuo Wei, Yehui Sun, Qiang Cheng, Sumanta Chatterjee, Zachary Traylor, Lindsay T Johnson, Melissa L Coquelin, Jialu Wang, Michael J Torres, Xizhen Lian, Xu Wang, Yufen Xiao, Craig A Hodges, Daniel J Siegwart.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

DOI: https://doi.org/10.1038/s41467-023-42948-2
Mol Pharm. 2023 Nov 17.

Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions.

Anne-Gaëlle Reinhart, Anja Osterwald, Philippe Ringler, Yael Leiser, Matthias E Lauer, Rainer E Martin, Christoph Ullmer, Felix Schumacher, Claudia Korn, Michael Keller.

  mRNA LNPs can experience a decline in activity over short periods (ranging from weeks to months). As a result, they require frozen storage and transportation conditions to maintain their full functionality when utilized. Currently approved commercially available mRNA LNP vaccines also necessitate frozen storage and supply chain management. Overcoming this significant inconvenience in the future is crucial to reducing unnecessary costs and challenges associated with storage and transport. In this study, our objective was to illuminate the potential time frame for nonfrozen storage and transportation conditions of mRNA LNPs without compromising their activity. To achieve this goal, we conducted a stability assessment and an in vitro cell culture delivery study involving five mRNA LNPs. These LNPs were constructed by using a standard formulation similar to that employed in the three commercially available LNP formulations. Among these formulations, we selected five structurally diverse ionizable lipids─C12-200, CKK-E12, MC3, SM-102, and lipid 23─from the existing literature. We incorporated these lipids into a standard LNP formulation, keeping all other components identical. The LNPs, carrying mRNA payloads, were synthesized by using microfluidic mixing technology. We evaluated the shelf life stability of these LNPs over a span of 9 weeks at temperatures of 2-8, 25, and 40 °C, utilizing an array of analytical techniques. Our findings indicated minimal impact on the hydrodynamic diameter, zeta potential, encapsulation efficiency, and polydispersity of all LNPs across the various temperatures over the studied period. The RiboGreen assay analysis of LNPs showed consistent mRNA contents over several weeks at various nonfrozen storage temperatures, leading to the incorrect assumption of intact and functional LNPs. This misunderstanding was rectified by the significant differences observed in EGFP protein expression in an in vitro cell culture (using HEK293 cells) across the five LNPs. Specifically, only LNP 1 (C12-200) and LNP 4 (SM-102) exhibited high levels of EGFP expression at the start (T0), with over 90% of HEK293 cells transfected and mean fluorescence intensity (MFI) levels exceeding 1. Interestingly, LNP 1 (C12-200) maintained largely unchanged levels of in vitro activity over 11 weeks when stored at both 2-8 and 25 °C. In contrast, LNP 4 (SM-102) retained its functionality when stored at 2-8 °C over 11 weeks but experienced a gradual decline of in vitro activity when stored at room temperature over the same period. Importantly, we observed distinct LNP architectures for the five formulations through cryo-EM imaging. This highlights the necessity for a deeper comprehension of structure-activity relationships within these complex nanoparticle structures. Enhancing our understanding in this regard is vital for overcoming storage and stability limitations, ultimately facilitating the broader application of this technology beyond vaccines.

Keywords:  EGFP; LC-MS; LNP; analytics; electron microscopy; mRNA; shelf-life; stability

DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00956
Biomacromolecules. 2023 Nov 13.

Cationic Starch Nanoparticles for Enhancing CpG Oligodeoxynucleotide-Mediated Antitumor Immunity.

Jiawen Zhang, Shuo Wang, Honghui Huang, Hongqian Chen, Jinghua Chen, Huijie Zhang.

CpG ODNs demonstrate a significant promise for immunotherapy. However, their application is limited owing to quick DNase digestion and inadequate cellular internalization. Transportation of CpG ODNs into immune cells is crucial. Although viral vectors exhibit high transfection efficiency, safety risks, high cost, and low carrying capacity remain big obstacles. Herein, a novel CpG ODNs vector was fabricated by using starch. Starch was ultrasonicated and simply aminated (NH2-St) through grafting with diethylenetriamine, which was spherical with a diameter of 50 nm. NH2-St possessed good biocompatibility. Cationic NH2-St encapsulated CpG ODNs well and possessed a high loading capacity of 317 μg/mg. NH2-St protected CpG ODNs from nuclease digestion and significantly enhanced their cellular uptake. NH2-St/CpG induced the potent secretion of antitumor cytokines from macrophages and effectively suppressed the growth of tumor cells. This work highlights the promise of starch for CpG ODNs delivery, which brings new hope for cancer immunotherapy.

DOI: https://doi.org/10.1021/acs.biomac.3c00917
J Nanobiotechnology. 2023 Nov 14. 21(1): 420

Synergetic regulation of cancer cells and exhausted T cells to fight cold tumors with a fluorinated EGCG-based nanocomplex.

Jinlin Zhang, Mingyue Wang, Doudou He, Liang Zhang, Tianqing Liu, Kaikai Wang.

  Immune therapy that targets PD-L1 (programmed cell death-ligand 1) is attractive to augment immune response by breaking the programmed cell death-1 (PD-1)/PD-L1 axis. However, T cell exhaustion associated with insufficient T cells infiltration may diminish the efficacy of cancer therapy. Here, we report a novel delivery system of FEGCG/FPEI@siTOX composed of fluorinated EGCG (FEGCG) and fluorinated polyethyleneimine (FPEI) for delivery of small interfering RNA anti-TOX (thymus high mobility group box protein, TOX) to treat tumor and metastasis. In this way, the reduction in PD-L1 expression by FEGCG can promote T-cell function, while inhibition of TOX expression with siTOX can alleviate T-cell exhaustion. FPEI are designed to deliver siRNA with high efficiency and low toxicity compared to classical PEI. Integrating FEGCG, FPEI and siTOX into such a novel system resulted in excellent anti-tumor and antimetastatic effects. It is a promising delivery system and potential strategy for the treatment of "cold" tumors.

Keywords:  Delivery system; EGCG; Immunotherapy; Programmed death-ligand 1

DOI:  https://doi.org/10.1186/s12951-023-02205-6
Sci Rep. 2023 Nov 17. 13(1): 20175

Surface functionalization affects the retention and bio-distribution of orally administered mesoporous silica nanoparticles in a colitis mouse model.

Roman Schmid, Meta Volcic, Stephan Fischer, Zhi Qu, Holger Barth, Amirali Popat, Frank Kirchhoff, Mika Lindén.

Besides the many advantages of oral drug administration, challenges like premature drug degradation and limited bioavailability in the gastro-intestinal tract (GIT) remain. A prolonged residence time in the GIT is beneficial for enhancing the therapeutic outcome when treating diseases associated with an increased intestinal clearance rate, like inflammatory bowel disease (IBD). In this study, we synthesized rod-shaped mesoporous silica nanoparticles (MSNs) functionalized with polyethylene glycol (PEG) or hyaluronic acid (HA) and investigated their bio-distribution upon oral administration in vivo. The negatively charged, non-toxic particles showed different accumulation behavior over time in healthy mice and in mice with dextran sulfate sodium (DSS)-induced intestinal inflammation. PEGylated particles were shown to accumulate in the lower intestinal tract of healthy animals, whereas inflammation promoted retention of HA-functionalized particles in this area. Overall systemic absorption was low. However, some particles were detected in organs of mice with DSS-induced colitis, especially in the case of MSN-PEG. The in vivo findings were connected to surface chemistry-related differences in particle adhesion on Caco-2/Raji and mucus-producing Caco-2/Raji/HT29 cell co-culture epithelial models in vitro. While the particle adhesion behavior in vivo was mirrored in the in vitro results, this was not the case for the resorption results, suggesting that the in vitro model does not fully reflect the erosion of the inflamed epithelial tissue. Overall, our study demonstrates the possibility to modulate accumulation and retention of MSNs in the GIT of mice with and without inflammation through surface functionalization, which has important implications for the formulation of nanoparticle-based delivery systems for oral delivery applications.

DOI: https://doi.org/10.1038/s41598-023-47445-6
Chem Commun (Camb). 2023 Nov 13.

Frontiers in nonviral delivery of small molecule and genetic drugs, driven by polymer chemistry and machine learning for materials informatics.

Jeffrey M Ting, Teresa Tamayo-Mendoza, Shannon R Petersen, Jared Van Reet, Usman Ali Ahmed, Nathaniel J Snell, John D Fisher, Mitchell Stern, Felipe Oviedo.

Materials informatics (MI) has immense potential to accelerate the pace of innovation and new product development in biotechnology. Close collaborations between skilled physical and life scientists with data scientists are being established in pursuit of leveraging MI tools in automation and artificial intelligence (AI) to predict material properties in vitro and in vivo. However, the scarcity of large, standardized, and labeled materials data for connecting structure-function relationships represents one of the largest hurdles to overcome. In this Highlight, focus is brought to emerging developments in polymer-based therapeutic delivery platforms, where teams generate large experimental datasets around specific therapeutics and successfully establish a design-to-deployment cycle of specialized nanocarriers. Three select collaborations demonstrate how custom-built polymers protect and deliver small molecules, nucleic acids, and proteins, representing ideal use-cases for machine learning to understand how molecular-level interactions impact drug stabilization and release. We conclude with our perspectives on how MI innovations in automation efficiencies and digitalization of data-coupled with fundamental insight and creativity from the polymer science community-can accelerate translation of more gene therapies into lifesaving medicines.

DOI: https://doi.org/10.1039/d3cc04705a
Biomacromolecules. 2023 Nov 16.

Simply and Cheaply Prepared Liposomal Membrane for Nanocarriers: High Encapsulation Efficiency Based on Broad Regulation of Surface Charges and pH-Switchable Performance.

Jiangjie Wu, Xin Zhang, Huili Yuan, Sailong Wei, Xiaokai Gu, Yangfan Bu, Huiwen He, Yanqin Shi, Meng Ma, Si Chen, Xu Wang.

The zeta potential of nanoparticles impacts their distribution and metabolism in the body as well as their interaction with medications of varying charges, hence altering therapeutic efficacy and safety. In this paper, the external charges of liposomes were regulated by utilizing a simple and economical method based on competition for protons of cationic chitosan (CS) and anion hyaluronic acid (HA). The charge regulation of a liposomal membrane is generally accomplished by adjusting the ratio of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS), the stability of which was maintained by the coating materials of cationic chitosan (CS) or anion hyaluronic acid (HA). A series of nanoparticles could respond to pH-stimulation with adjustable surface charge. Moreover, the sizes of liposomes coated with CS and HA remain within a narrow range. In vitro cytotoxicity tests revealed that the nanocarriers were safe, and the nanoparticles containing antitumor medicines were efficient in tumor therapy. Considering liposomes with different external surface charges could be aimed at diverse therapy purposes. The strategies for regulating liposomal surface charges with high encapsulation rates and certain release cycles reported here could provide a versatile platform as carriers for the delivery of drugs and other macromolecules into human bodies.

DOI: https://doi.org/10.1021/acs.biomac.3c00679