A photoresponsive antibody–siRNA conjugate for activatable immunogene therapy of cancer |
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Authors: | Xingxing Wang Xiao Xiao Yi Feng Jinbo Li Yan Zhang |
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Institution: | State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023 China, |
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Abstract: | Tumor-targeted delivery of small-interfering RNAs (siRNAs) for cancer therapy still remains a challenging task. While antibody–siRNA conjugates (ARCs) provide an alternative way to address this challenge, the uncontrollable siRNA release potentially leads to undesirable off-tumor side effects, limiting their in vivo therapeutic efficacy. Here, we report a photoresponsive ARC (PARC) for tumor-specific and photoinducible siRNA delivery as well as photoactivable immunogene therapy. PARC is composed of an anti-programmed death-ligand 1 antibody (αPD-L1) conjugated with a siRNA against intracellular PD-L1 mRNA through a photocleavable linker. After targeting cancer cells through the interaction between αPD-L1 and membrane PD-L1, PARC is internalized and it liberates siPD-L1 upon light irradiation to break the photocleavable linker. The released siPD-L1 then escapes from the lysosome into the cytoplasm to degrade intracellular PD-L1 mRNA, which combines the blockade of membrane PD-L1 by αPD-L1 to boost immune cell activity. Owing to these features, PARC causes effective cancer suppression both in vitro and in vivo. This study thus provides a useful conditional delivery platform for siRNAs and a novel means for activatable cancer immunogene therapy.A photoresponsive antibody–siRNA conjugate (PARC) enables tumor-targeted siRNA delivery and photoactivatable gene silencing for cancer immunotherapy. |
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