Smart Supramolecular “Trojan Horse”‐Inspired Nanogels for Realizing Light‐Triggered Nuclear Drug Influx in Drug‐Resistant Cancer Cells

Efficient nuclear delivery of anticancer drugs evading drug efflux transporters (DETs) on the plasma and nuclear membranes of multidrug‐resistant cancer cells is highly challenging. Here, smart nanogels are designed via a one‐step self‐assembly of three functional components including a biocompatible copolymer, a fluorescent organosilica nanodot, and a photodegradable near‐infrared (NIR) dye indocyanine green (ICG). The rationally designed nanogels have high drug encapsulation efficiency (≈99%) for anticancer drug doxorubicin (Dox), self‐traceability for bioimaging, proper size for passive tumor targeting, prolonged blood circulation time for enhanced drug accumulation in tumor, and photocontrolled disassemblability. Moreover, the Dox‐loaded nanogels can effectively kill multidrug‐resistant cells via two steps: 1) They behave like a “Trojan horse” to escape from the DETs on the plasma membrane for efficiently transporting the anticancer “soldier” (Dox) into the cytoplasm and preventing the drugs from being excreted from the cells; 2) Upon NIR light irradiation, the photodegradation of ICG leads to the disassembly of the nanogels to release massive Dox molecules, which can evade the DETs on the nuclear membrane to exert their intranuclear efficacy in multidrug‐resistant cells. Combined with their excellent biocompatibility, the nanogels may provide an alternative solution for overcoming cancer multidrug resistance. A smart supramolecular nanogel is constructed to circumvent cancer multidrug resistance. The nanogel behaves like a “Trojan horse” to escape from the drug efflux transporters (DETs) on the plasma membrane for efficiently transporting drugs into the cytoplasm. Meanwhile, through a light‐triggered strategy, massive drugs can be quickly released, thus realizing nuclear drug influx by evading the DETs on the nuclear membrane.