Study On Structure-Property Relationship And Application Of Dense Shell Nanoparticles With Membrane Anchoring Function

Organometallic catalyst mediated bioorthogonal transformation has shown great potential in synthetic biology and pharmaceutical chemistry.In particular,the intracellular synthesis and activation of drugs using biocompatible metal catalysts has attracted wide attention of researchers.Although this is an attractive approach for biological and medical research,intracellular synthesis or activation of drugs does not provide therapeutic benefits compared to the corresponding drugs alone,which limits the practical application of this approach.In this paper,we attempt to utilize previously reported cationic dense shell nanoparticles(DSNPs)as membrane anchoring catalysts(MAC)for more efficient drug synthesis in cells.In previous work,we found that DSNPs had very good membrane targeting effects,which meant that the topologies of organic nanoparticles could work in concert with functional groups to provide unique membrane affinity and enable abiocatalysis in cell membranes.However,due to the lack of systematic studies on the structure-performance relationship of DSNP,such synergies could not be well understood and utilized,and there were not enough data to guide the optimization of DSNP structure for more complex applications.To solve this problem,we adopted a bottom-up strategy to construct DSNP structures with different parameters,including size,charge density and type of charged part,using monomers that are easy to synthesize.Flow cytometry and confocal laser microscopy were used to investigate the effects of different parameters on cellular uptake,membrane affinity,cytotoxicity and catalytic activity of these DSNPs.We applied DSNP with different parameters to bacteria,studied the anchoring effect of DSNP on bacterial membrane,and selected the imidazolium salt-DSNP with the best anchoring effect on bacterial membrane.We used bacteria as the carrier of imidazolium salt-DSNP to load DSNP onto bacteria and enter cells for catalysis.The results showed that the catalytic product was successfully generated,indicating the successful establishment of the model of bacteria as DSNP carrier.In the DSNP structural system with different parameters,we used the phosphorus-rich DSNP with the best performance in the cell as the membrane anchoring catalyst.Through three model experiments,we proved that molecules with low cell permeability can be obtained by catalytic coupling of precursor molecules on the membrane.In contrast to previous studies on intracellular catalysis,in our work,reagents prepared by on-membrane catalysis showed superior efficacy compared with the corresponding pure reagent directly incubated,suggesting that the MAC strategy can be used to address the membrane permeability problem of drugs.We also preliminarily studied the selectivity of DSNP to different substrates,and found that DSNP had better selectivity to substrates with more hydrophobic and higher charge force in cells.