Effective nanomedicines need to overcome complex biological and pathological barriers to exert desired therapeutic effects. Current strategies are to integrate various requisite components into one nanomedicine, inevitably complicating nanomedicines’ structures and thus hindering their clinical translation. Here, we report a series of zwitterionic polymeric micelles made of poly (ε-caprolactone)-<i>block</i>-poly(sulfobetaine methacrylate) (PCL-PSBMA) as carriers for efficient cancer drug delivery. By varying the alkyl chain length of the N-substituent on sulfobetaine, PCL-PSBMA micelles are optimized to exhibit non-stickiness towards proteins, appropriate cell-membrane affinity, and superior transcytosis behavior. PCL-PSBMA micelles hitchhiked on red blood cells to circulate long in blood and reversibly adsorbed on the tumor endothelial cells and then tumor cells to enable transcytosis-mediated blood vessel extravasation and tumor penetration. As a result, the PTX-loaded micelles achieved potent antitumor efficacy in orthotropic hepatocellular carcinoma and breast cancer models. This work provides simple but omnipotent zwitterionic micelles as a generic drug delivery platform, possibly holding great potential in clinical translation.

Polysulfobetaine-derived zwitterionic micelles with appropriate cell-membrane affinity for efficient cancer drug delivery

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