Intracellular Delivery of Functional Native Antibodies under Hypoxic Conditions by Using a Biodegradable Silica Nanoquencher

Antibodies are important biopharmaceuticals, but almost all existing antibody‐based drugs are limited to targeting antigens located at the cell exterior because of the inability of antibodies to enter the cell interior. Available methods for intracellular delivery of antibodies have major shortcomings. Herein, we report an approach to encapsulate native antibodies in a biodegradable silica nanoquencher (BS‐qNP), which could undergo efficient cellular uptake and intracellular degradation to release antibodies only under hypoxic conditions. By coating the surface of BS‐qNP with cell‐penetrating poly(disulfide)s (CPD), the delivered antibodies (or other proteins) avoided endolysosomal trapping. Doping of the silica coating with a fluorescent dye and a dark hole quencher further endowed BS‐qNP with hypoxia‐responsive fluorescence turn‐on property. Our antibody delivery system thus provides the first platform capable of stable encapsulation, efficient uptake, on‐demand antibody release, and imaging of release/cell state. Better delivery is possible: The first hypoxia‐responsive antibody‐encapsulated silica nanoquencher was developed to achieve endocytosis‐independent cell uptake and on‐demand intracellular release of native therapeutic antibodies in cancer cells, with the capability to simultaneously image both antibody release and hypoxic state of cells.