Our group studies the mechanisms of peptide-mediated delivery of macromolecules into living cells focussing on delivering novel drug modalities. We examine the mechanisms that modified Cell-Penetrating Peptides (CPP) harness for non-invasively transducing into living cells nucleic acids (NA) with therapeutic potential, like siRNA, miRNA, SCO, pDNA, etc. and regulating the expression of targeted genes. For that, we aim unravelling the principles behind the assembly of efficacious CPP-NA nanoparticles (NP) by analysing their physical-chemical characteristics and correlating with biological activity in tissue cultures and animal models.
We have focussed on the elucidation of molecules on the cell surface and in the plasma membrane that govern the association of CPPs with cells, translocation across the membranes and induce internalisation of cargo molecules. By harnessing various microscopy techniques (FM, CLSM, TEM) we map the cell-entry mechanisms (various endocytosis routes) and trafficking of NPs inside cells (escape from endosomes and translocation into nucleus). The intruders like viruses, bacteria and administered NPs are recognised by living organism as a threat, and are coated with protein corona (PC) for segregation and degradation. We analyse the composition of PC on CPP-NA particles and modulate it in order to increase their efficacy and gain specificity toward targeted cells/tissue. In parallel, we elaborate the strategies for liberation of NP from entrapping endosomes/lysosomes and inhibiting autophagy.
In collaboration with research groups of medical department, we therapeutically modulate the expression of target genes in human primary cells and in animal models of dermatitis and psoriasis with CPP-miRNA/siRNA NP. With collaborating groups, we harness cationic polymers and lipids for packing siRNA into NPs and for delivering into cells, and specifically targeting to induced tumours in animal models.
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