Abstract The blood‐brain barrier (BBB) poses a significant challenge in delivering therapeutic agents for brain diseases due to its high selectivity against foreign substances. This limitation greatly hampers the effectiveness of conventional chemotherapeutic drugs in treating brain cancers. In response, lipid‐based nanoparticles (LNPs) have emerged as a promising approach, offering opportunities for targeted drug delivery by conjugating targeting ligands onto their surface. This review provides a comprehensive overview of recent advancements in utilizing LNPs to traverse the BBB for enhanced transport of bioactive compounds into the brain, specifically for cancer treatments. Beginning with an exploration of the biological structure and functions of the BBB and the blood‐brain tumor barrier (BBTB), the review highlights the advantages presented by LNPs. Subsequently, it delves into strategies for surface modification of nanoparticles to enhance BBB targeting and improve efficacy in brain cancer treatment. Finally, the review offers insights into future prospects for designing the next generation of LNPs. The review presented herein aims to contribute to the ongoing efforts in overcoming the challenges associated with BBB penetration, ultimately advancing therapeutic strategies for brain cancer and other neurological disorders.
Ionisable amino-lipid is a key component in lipid nanoparticles (LNPs), which plays a crucial role in the encapsulation of RNA molecules, allowing efficient cellular uptake and then releasing RNA from acidic endosomes. Herein, we present direct evidence for the remarkable structural transitions, with decreasing membrane curvature, including from inverse micellar, to inverse hexagonal, to two distinct inverse bicontinuous cubic, and finally to a lamellar phase for the two mainstream COVID-19 vaccine ionisable ALC-0315 and SM-102 lipids, occurring upon gradual acidification as encountered in endosomes. The millisecond kinetic growth of the inverse cubic and hexagonal structures and the evolution of the ordered structural formation upon ionisable lipid-RNA/DNA complexation are quantitatively revealed by in situ synchrotron radiation time-resolved small angle X-ray scattering coupled with rapid flow mixing. We found that the final self-assembled structural identity, and the formation kinetics, were controlled by the ionisable lipid molecular structure, acidic bulk environment, lipid compositions, and nucleic acid molecular structure/size. The implicated link between the inverse membrane curvature of LNP and LNP endosomal escape helps future optimisation of ionisable lipids and LNP engineering for RNA and gene delivery.
Abstract Ionisable amino‐lipid is a key component in lipid nanoparticles (LNPs), which plays a crucial role in the encapsulation of RNA molecules, allowing efficient cellular uptake and then releasing RNA from acidic endosomes. Herein, we present direct evidence for the remarkable structural transitions, with decreasing membrane curvature, including from inverse micellar, to inverse hexagonal, to two distinct inverse bicontinuous cubic, and finally to a lamellar phase for the two mainstream COVID‐19 vaccine ionisable ALC‐0315 and SM‐102 lipids, occurring upon gradual acidification as encountered in endosomes. The millisecond kinetic growth of the inverse cubic and hexagonal structures and the evolution of the ordered structural formation upon ionisable lipid‐RNA/DNA complexation are quantitatively revealed by in situ synchrotron radiation time‐resolved small angle X‐ray scattering coupled with rapid flow mixing. We found that the final self‐assembled structural identity, and the formation kinetics, were controlled by the ionisable lipid molecular structure, acidic bulk environment, lipid compositions, and nucleic acid molecular structure/size. The implicated link between the inverse membrane curvature of LNP and LNP endosomal escape helps future optimisation of ionisable lipids and LNP engineering for RNA and gene delivery.
Antimicrobial resistance (AMR) poses a global health crisis demanding innovative solutions. Traditional antibiotics, though pivotal over the past century in combating bacterial infections, face diminished efficacy against evolving bacterial defense mechanisms, especially in Gram‐negative strains. This study explores self‐assembled ionizable lipid nanoparticles (LNPs) with the incorporation of two ionizable lipid components (one cationic, one anionic) in nanocarriers for advanced antimicrobial drug delivery of the broad‐spectrum antibiotic Piperacillin (Pip). Incorporating cationic ionizable lipid ALC‐0315, recognized as a functional lipid in the Pfizer‐BioNTech mRNA‐based SARS‐CoV‐2 vaccine, into LNPs allowed mesophase transition, pH responsiveness, and ionization behavior in acidic environments found in sites of bacterial infections, to be studied using synchrotron small angle X‐ray scattering, dynamic light scattering, and a 2‐(p‐toluidino)‐6‐naphthalene sulfonic acid assay. Incorporating another anionic ionizable lipid, oleic acid not only modulates the LNPs’ physicochemical properties, such as size, internal phase nanostructure, and surface charge but also synergistically enhances the antimicrobial potency together with ALC‐0315 with a benefit enhancing permeability and fusion with bacterial membranes. This study introduces a strategy for tailoring ionizable lipid compositions in LNPs, providing a new approach to antimicrobial treatment contributing to the fight against AMR.
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