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ABSTRACT
Introduction: The whole delivery process of nucleic acids is very challenging. Appropriate carrier systems are needed, which show extracellular stability and intracellular disassembly. Viruses have developed various strategies to meet these requirements, as they are optimized by biological evolution to transfer genetic information into host cells. Taking viruses as models, smart synthetic carriers can be designed, mimicking the efficient delivery process of viral infection. These ‘synthetic viruses’ are pre-programmed and respond to little differences in their microenvironment, caused by either exogenous or endogenous stimuli.
Areas covered: This review deals with polymer-based, bioresponsive nanosystems (polyplexes) for the delivery of nucleic acids. Strategies utilizing pH-responsiveness, redox-responsiveness as well as sensitivity towards enzymes will be described more in detail. Systems, which respond to other endogenous triggers (i.e. reactive oxygen species, adenosine triphosphate, hypoxia), will be briefly illustrated. Moreover, some examples for combined bioresponsiveness will be presented.
Expert opinion: Bioresponsive polyplexes are a smart way to facilitate programmed, timely delivery of nucleic acids to desired, specific sites. Nevertheless, further optimization is necessary to improve the still moderate transfection efficiency and specificity – also in regard to medical translation. For this purpose, precise carrier structures are desirable and stability issues of bioresponsive systems must be considered.
Acknowledgments
We are greatly thankful for support of our work by German Research Foundation (DFG) DFG SFB1032 B4 and SFB1066 B5 as well as the DFG Excellence Cluster Nanosystems Initiative Munich (NIM).
Article highlights
Just like their natural counterparts, ‘artificial, synthetic viruses’ should be responsive to changes in microenvironment, caused by either exogenous or endogenous stimuli (physical or biochemical targeting).
Bioresponsive triggers include changes in pH value, redox-potential, enzyme-sensitivity, varying levels of ROS or ATP, or hypoxia.
Triggered conformational changes or bond cleavages lead to activation or exposure of functional domains or to breakdown of the nanocarrier.
Bioresponsiveness enables programmed, timely delivery of nucleic acids to specific sites, as well as reduced cytotoxicity of the carrier, and thus can enhance both transfer efficiency and biocompatibility.
By combining two and more (bio)responsive moieties in one nanocarrier, even better mimicking of the dynamic, stepwise process of viral infection can be achieved.
Further optimization of non-viral carriers including their precise manufacture and storage in the stable form is required, also in regard to medical translation.
This box summarizes key points contained in the article.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.