Progress in mRNA delivery systems based on virus-like particles
In the past few years,the global COVID-19 pandemic has led to widespread attention to mRNA therapy,with the emergence of the mRNA COVID-19 vaccine driving the rapid development of mRNA therapeutics.mRNA has shown great and unique potential in vaccine development,protein replacement therapy,and gene editing,which,however,has been limited by issues such as poor stability,inability to enter cells autonomously,low translation efficiency,and immune stimulation activity.With a deepening understanding of mRNA structure and continuous progress in mRNA synthesis and modification-related technologies,optimization of the cap structure,5'-and 3'-untranslated regions,open reading frame,and poly(A)tail have been implemented to enhance mRNA stability,increase its expression levels in vivo,and reduce immune stimulation.Efficient mRNA delivery into target cells to enable high-level translation has always been a major problem in mRNA therapy.Developing safe and efficient delivery vectors has been a central pursuit to solve the problem.Based on the source of their composition,mRNA delivery vectors can be divided into two categories:Non-viral and viral.Non-viral vectors include lipid nanoparticles,polymers,extracellular vesicles,and peptides.The most commonly used is the lipid nanoparticles.However,problems with this non-viral vector remain,such as cell toxicity and the inability to target specific tissues.Viruses are natural vehicles for nucleic acid delivery.Viral mRNA vectors include lentivirus vectors,adenovirus vectors,adeno-associated virus(AAV)vectors,and virus-like particles(VLPs).VLPs have many beneficial features as mRNA vectors,such as uniform morphology,the activity of entering target cells,having three interfaces for modification,biocompatibility,biodegradability,and scalable production.According to whether they have a lipid membrane,VLPs are classified as enveloped or non-enveloped.In this review,the recent progress of mRNA delivery by VLPs is summarized.Specifically,cowpea chlorotic mottle virus(CCMV)VLP and bacteriophage MS2 VLP,which represent the non-enveloped VLP group,are first introduced.Lentivirus and alphavirus representing enveloped VLPs are described in the following sections.In each section,structural features closely related to the immunogenicity and biodistribution of VLPs such as structural composition,icosahedral arrangement,genome components,and surface chemistry,are discussed.Based on the structural features,the mechanisms for packaging and delivering mRNA drugs by VLPs are explained respectively.The fundamental studies and applications of VLP-based mRNA delivery systems in cancer immunotherapy,antiviral vaccines,and gene editing are also mentioned.Moreover,an emerging group of de novo-designed artificial VLPs is introduced in the last section.The application of artificial VLPs has opened up new possibilities for efficient mRNA delivery.They will benefit the platforms for mRNA therapy in the near future.Contributions of VLP-based mRNA delivery systems are expanding the frontier of gene therapy by nanocarriers.It should be noted that the regulation of mRNA delivery and translation efficiency still needs to be improved.Considering continuous multidisciplinary efforts in this field,we anticipate a promising future of mRNA therapy in VLP-based nanomedicine.
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