Multi‐Responsive Molecularly Imprinted Polymer Nanocapsules as Biological Environment‐Adaptable Drug Carriers for Efficient Cancer Therapy

Biological environment-adaptable polymer nanocapsules capable of overcoming multiple biological barriers and efficiently realizing on-demand drug delivery to the target tumor cells are highly promising for cancer therapy, but their development remains challenging. Herein, the efficient synthesis of well-defined multi-responsive hydrophilic hairy fluorescent molecularly imprinted polymer (MIP) nanocapsules is reported to address this issue, which have a disulfide-crosslinked fluorescent MIP shell with sialic acid (SA, generally overexpressed on tumor cells)-imprinted binding sites, some poly(methacrylic acid) chains inside cavities, and surface-grafted (via dynamic benzoic-imine bond) block copolymer brushes with a thermo/pH-responsive (collapse/stretching) inner block and a hydrophilic outer block. They show excellent aqueous dispersity, good bio/hemocompatibility, and tumor-microenvironment-triggered detachment of polymer brushes (allowing exposure of SA-imprinted sites and negative-to-positive surface charge reversal) and (glutathione-induced) degradation. Particularly, they also exhibit integrated properties of an ultrahigh antitumor drug (5-fluorouracil) loading capacity (688 µmol g^-1), negligible premature drug release, largely prolonged blood circulation, specific and sustainable tumor site accumulation, enhanced tumor penetration, and rapid drug release inside tumor cells, which enable them to significantly inhibit tumor growth inside mice. This study opens new access for well-tailored smart "all-in-one"-type drug carriers as a versatile nanoplatform for various cancer therapies by simply loading different or multiple drugs.