There is an unmet need for carriers that can deliver nucleic acids (NAs) to cancer cells and tumors to perpetuate gene regulation and manage disease progression. Membrane-wrapped nanoparticles (NPs) can be loaded with exogenously designed nucleic acid cargoes, such as plasmid deoxyribonucleic acid (pDNA), messenger ribonucleic acid (mRNA), small interfering RNA (siRNA), microRNA (miRNA), and immunostimulatory CpG oligodeoxynucleotides (CpG ODNs), to mitigate challenges presented by NAs’ undesirable negative charge, hydrophilicity, and relatively large size. By conjugating or encapsulating NAs within membrane-wrapped NPs, various physiological barriers can be overcome so that NAs experience increased blood circulation half-lives and enhanced accumulation in intended sites. This review discusses the status of membrane-wrapped NPs as NA delivery vehicles and their advancement in gene regulation for cancer management in vitro and in vivo . With continued development, membrane-wrapped NPs have great potential as future clinical tools to treat cancer and other diseases with a known genetic basis.
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Rational design of engineered H-ferritin nanoparticles with improved siRNA delivery efficacy across an in vitro model of the mouse BBB
Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood–brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.
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- Award ID(s):
- 2001606
- NSF-PAR ID:
- 10410017
- Date Published:
- Journal Name:
- Nanoscale
- Volume:
- 14
- Issue:
- 17
- ISSN:
- 2040-3364
- Page Range / eLocation ID:
- 6449 to 6464
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1NR07880A
