Engineered targeting tLyp-1 exosomes as gene therapy vectors for efficient delivery of siRNA into lung cancer cells

Natural exosomes can express specific proteins and carbohydratemolecules on the surface and hence have demonstrated the great potentials for gene therapy of cancer.However,the use of natural exosomes is restricted by their low transfection efficiency.Here,we report a novel targeting tLyp-1 exosome by gene recombinant engineering for delivery of siRNA to cancer and cancer stem cells.To reach such a purpose,the engineered tLyp-1-lamp2b plasmids were constructed and amplified in Escherichia coli.The tLyp-1-lamp2b plasmids were further used to transfect HEK293T tool cells and the targeting tLyp-1 exosomes were isolated from secretion of the transfected HEK293T cells.Afterwards,the artificially synthesized siRNA was encapsulated into targeting tLyp-1 exosomes by electroporation technology.Finally,the targeting siRNA tLyp-1 exosomes were used to transfect cancer or cancer stem cells.Results showed that the engineered targeting tLyp-1 exosomes had a nanosized structure(approximately 100 nm)and high transfection efficiency into lung cancer and cancer stem cells.The function verifications demonstrated that the targeting siRNA tLyp-1 exosomes were able to knock-down the target gene of cancer cells and to reduce the stemness of cancer stem cells.In conclusion,the targeting tLyp-1 exosomes are successfully engineered,and can be used for gene therapy with a high transfection efficiency.Therefore,the engineered targeting tLyp-1 exosomes offer a promising gene delivery platform for future cancer therapy.

Switchable nanoparticles complexing cisplatin for circumventing glutathione depletion in breast cancer chemotherapy

Cisplatin is broad-spectrum chemotherapeutic agent that has been widely used for the treatment of a variety of malignant tumors including breast cancer.However,the cisplatin chemoresistance,which derives from the inactivation by glutathione(GSH)depletion,remains a scientific issue to solve.Here,we report a novel type of smart disulfide switchable nanoparticles complexing cisplatin(switch NPs-cisplatin)that is rationally designed,and engineered by synthesizing a hyaluronic acid disulfide bonded polyaspartic acid(HA-ss-Pasp)and complexing cisplatin.The results showed that the switch NPs-cisplatin had a nanoscale of particle size(150 nm),higher drug encapsulation efficiency(>90%),and suitable drug release profile.They demonstrated evident pH responsiveness and GSH responsiveness,and targeting effect in the resistant breast cancer cells.Furthermore,they were able to block the cisplatin depletion by GSH in the resistant cancer cells,thereby circumventing the chemoresistance.Consequently,switch NPs-cisplatin displayed a remarkable killing effect in the resistant breast cancer cells in vitro,and in the resistant breast cancer-bearing mice.In conclusion,switch NPs-cisplatin could be used as a smart formulation of cisplatin for overcoming the chemoresistance of breast cancer.The present study also offers a universal drug delivery carrier platform for highly efficient but low systemic toxic chemotherapy.