Role of size, surface charge, and PEGylated lipids of lipid nanoparticles (LNPs) on intramuscular delivery of mRNA.

Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs.

Mechanism and performance of choline-based ionic liquids in enhancing nasal delivery of glucagon.

Proteins and peptides have been increasingly developed as pharmaceuticals owing to their high potency and low side effects. However, their administration routes are confined to injections, such as intra-muscular and intra-venous injections, making patient compliance a challenge. Hence, non-injectable delivery systems are crucial to expanding the clinical use of proteins and peptides. In this context, two choline-based ionic liquids (ILs), namely, choline geranic acid ([Ch][Ger]) and choline citric acid ([Ch][Cit]), have been identified as promising agents for enhancing the permeation and prolonging the retention time of glucagon (GC) after intra-nasal administration. Notably, intra-nasal delivery of GC via ILs (GC/ILs) elicited rapid and smooth reversal of acute hypoglycaemia without leading to rebound hyperglycaemia in type 1 diabetic rats subjected to insulin induction. In addition, ILs could improve the transcellular transport of GC through electrostatic interaction. ILs could also transiently open inter-cellular tight junctions transiently to facilitate the paracellular transport of GC. Safety tests indicated that continuous intra-nasal delivery of ILs led to reversible changes, such as epithelial cell inflammation, goblet cell overgrowth, and impacts on the distribution of nasal cilia. However, these changes could be alleviated by the innate self-repair ability of mucosal epithelial cells. This study highlights the considerable potential of ILs for long-term nasal delivery of biomacromolecules.

The Role of Nanoparticle Morphology on Enhancing Delivery of Budesonide for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease that affects the gastrointestinal tract. The major hurdles impeding IBD treatment are the low targeting efficiency and short retention time of drugs in IBD sites. Nanoparticles with specific shapes have demonstrated the ability to improve mucus retention and cellular uptake. Herein, mesoporous silica nanoparticles (MSNs) with various morphologies were used to deliver budesonide (BUD) for the treatment of IBD. The therapeutic efficacy is strongly dependent on their shapes. The system comprises different shapes of MSNs as carriers for budesonide (BUD), along with Eudragit S100 as the enteric release shell. The encapsulation of Eudragit S100 not only improved the stability of MSNs-BUD in the gastrointestinal tract but also conferred pH-responsive drug release properties. Then, MSNs efficiently deliver BUD to the colon site, and the special shape of MSNs plays a critical role in enhancing their permeability and retention in the mucus layer. Among them, dendritic MSNs (MSND) effectively reduced myeloperoxidase (MPO) activity and levels of inflammatory cytokines in the colon due to long retention time and rapid release in IBD sites, thereby enhancing the therapeutic efficacy against colitis. Given the special shapes of MSNs and pH-responsivity of Eudragit S100, BUD loaded in the voids of MSND (E@MSNs-BUD) could penetrate the mucous layer and be accurately delivered to the colon with minor side effects. This system is expected to complement current treatment strategies for the IBD.

Translation of ionic liquids to be enteric nanoparticles for facilitating oral absorption of cyclosporine A.

Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2 h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules.

Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations.

Targeting strategies of oral nano-delivery systems for treating inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of gastrointestinal tract with rising incidence. Established treatments of IBD are characterized by significantly adverse effects, insufficient therapeutic efficacy. Employing the oral nano-drug delivery systems for targeted therapy is capable of effectively avoiding systematic absorption and increasing local drug concentration, consequently leading to decreased adverse effects and improved therapeutic outcomes. This review gives a brief profile of pathophysiological considerations in terms of developing disease-directed drug delivery systems, then focuses on mechanisms and strategies of current oral nano-drug delivery systems, including size-, enzyme-, redox-, pH-, ligand-receptor-, mucus-dependent systems, and proposes the future directions of managements for IBD.

Effects on immunization of the physicochemical parameters of particles as vaccine carriers.

Vaccination has milestone significance for the prophylactic and complete elimination of infectious diseases. However, combating malignant infectious diseases, such as Ebola or HIV, remains a challenge. It is necessary to explore novel technologies to facilitate the immune profile of vaccines. Particles exhibit a remarkable ability to modulate sophisticated immunity because of their intrinsic adjuvanticity or codelivery with immunostimulatory molecules. Recently, particles have been broadly investigated as carriers for vaccine delivery. Their physicochemical parameters (e.g., size, shape, and surface chemistry) significantly influence their in vivo fate and subsequent immunization effect. Herein, we highlight several types of particulate carrier used in the delivery of vaccines. We also examine how to engineer the physical and chemical characteristics of particulate adjuvants to make them robust candidates for a versatile vaccine delivery platform.

Insight into the in vivo translocation of oral liposomes by fluorescence resonance energy transfer effect.

Liposomes have been broadly used in pharmaceutical field to overcome oral absorption barriers, such as gastric acid, tenacious mucus or intestinal epithelia. However, the concrete in vivo absorption mechanisms of liposomes are still indistinct. This study aims to visually elucidate the effect of particle size and surface characteristics on in vivo translocation of oral liposomes by fluorescence resonance energy transfer (FRET) effect. We fabricated liposomes of various sizes (100 nm, 200 nm and 500 nm) and surface characteristics (anionic, cationic and PEGylated) which are also labeled with FRET probes for discriminating the intact liposomes. We then investigated the in vivo fate of those different liposomes upon oral administration. Results showed that smaller conventional liposomes, cationic and PEGylated liposomes had longer retention time in digestive tract. Few intact liposomes were taken up by intestinal epithelial cells and none were found in circulation. In vivo pharmacokinetics revealed that the smaller, cationic or PEGylated liposomes had higher relative bioavailability. Similar retention time of various liposomes in blood circulation to control solution indicated that liposomes improved oral drug absorption by either prolonging contact time with gastrointestinal tract or increasing penetration ability through mucus barrier, instead of being absorbed integrally into circulation. This study offered new insight into developing highly effective liposomes for oral delivery.