Design And Application Of Cell-based Drug Delivery Systems

Drug delivery systems have been greatly improved over the years for various disease therapy as they can increase the solubility and stability of drugs,improve pharmacokinetic and targeting,and reduce toxicities.However,biological barriers prevent the accumulation of drug delivery systems specifically at diseased sites,resulting in limited benefit in clinical trials.Endogenous cells have innate properties for drug delivery,such as long circulation,nature stealth performance,and cross biological barriers.By combination the advantages of natural cells and synthetic polymers,it is hoped to overcome various biological barriers that encounter by nanoparticles upon intravenous administration,and improve the bioavailability of drugs.In this dissertation,we focused on the development of endogenous cell membrane or whole cell-based drug delivery system to enhance therapeutic effect for tumors and infections.The main content of this dissertation is described in two parts as below:1.Myeloid-derived suppressor cells(MDSCs)promote tumor immune escape through multiple mechanisms including suppressing antitumor activities of T lymphocytes.However,therapeutic abrogation of MDSCs often causes severe adverse effects,compensatory recruitment of alternative cell populations,and the multiplicity and complexity of relevant cytokines and receptors.Alternatively,suppressing the expansion and tumor trafficking of MDSCs may be a proficient and safe way for cancer treatment.Here we report that pseudo-neutrophil cytokine sponges(pCSs)can disrupt expansion and tumor trafficking of MDSCs and reverse immune tolerance.Coated with plasma membranes of neutrophils,phenotypically and morphologically similar to polymorphonuclear MDSCs(PMN-MDSCs),the nano-sized pCSs inherited most membrane receptors from the "parental" neutrophils,enabling the neutralization of MDSC-related cytokines.Upon pCSs administration,the expansion of MDSCs and their enrichment in peripheral lymphoid organs and tumors were reduced without the compensatory influx of alternative myeloid subsets.In murine breast cancer and melanoma syngeneic models,pCSs treatment dramatically increased the number of tumor-infiltrating T lymphocytes and restored their antitumor functions.In addition,combining pCSs with the programmed cell death protein 1(PD-1)immune checkpoint blockade synergistically suppressed tumor progression and prolonged animal survival.Overall,the pseudo-cell nano-platform opens up new paths toward effective cancer immunotherapy.2.Targeting specific blood cells by nanomedicines provide an improvement on drug bioavailability,yet the surface adsorbed protein corona conceals targeting ligands on nanoparticles and thereby intrude their interaction with cells.Herein,instead of resorting to the anti-fouling or intricate surface modifications,we exploit the "true protein corona identity" of nanoparticles and seek to develop a "voluntary opsonization" strategy to hitchhike neutrophils for cell-aided drug delivery.Specially,we discover that liposomes composed of inverse phosphocholine lipids(CP)can rapidly adsorb complement fragment iC3b,which mediates highly efficient neutrophil hijack in situ through the interaction with complement receptor 3.More importantly,the targetability of particle is cell-state dependent with only those neutrophils activated by acute inflammation display tremendous accessibility.After preying on abundant liposomes,activated neutrophils can migrate across the alveolar-capillary barrier and accumulate in the inflamed lung parenchyma within hours.Over there,neutrophils can either release liposomes concurrently with the formation of neutrophil extracellular traps or engulf the surrounding bacteria to confine both drug-loaded liposomes and bacteria for efficient bacteria killing,achieving remarkable infection treatment and low mortality.Overall,this work opens up new paths for manipulating nano-biointerfaces through exploiting the proteins coating on nanoparticles.