A Smart Nano‐Prodrug Platform with Reactive Drug Loading, Superb Stability, and Fast Responsive Drug Release for Targeted Cancer Therapy

: Nano-prodrugs usually involve a multistep synthesis which largely compromises their benefits. Here, a smart nano-prodrug platform with reactive drug loading, superb stability, and triggered drug release is reported for targeted melanoma therapy. cRGD-decorated polymersomal mertansine prodrug (cRGD-PS-DM1) is readily fabricated from cRGD-functionalized poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) with simultaneous loading of mertansine (DM1) via thiol-disulfide exchange reaction and disulfide cross-linking of polymersomal membrane. cRGD-PS-DM1 exhibits a size of ≈100 nm, little drug leakage, and fast DM1 release in the presence of 2 × 10-3 -10 × 10-3 m glutathione. Tetrazolium-based colorimetric assay (MTT) and confocal microscopy studies confirm effective homing of cRGD-PS-DM1 to αv β3 overexpressing B16F10 melanoma cells. Notably, the in vivo studies show that cRGD-PS-DM1 has a greatly improved toleration as compared with free DM1 and effectively inhibits tumor growth and extends the survival time of B16F10 melanoma-bearing mice. cRGD-PS-DM1 nano-prodrug with reactive drug loading and multifunction provides an advanced nanomedicine for cancer therapy.