Protein‐Nonfouling and Cell‐Binding Polysulfobetaine Inducing Fast Transcytosis for Tumor‐Active Drug Delivery

Long blood circulation and fast cellular uptake are essential yet paradoxical requirements for efficient tumor-targeted drug delivery carriers. For instance, polyzwitterions, generally nonfouling to proteins and cells, have been extensively explored as long-circulating drug delivery carriers but suffer ultraslow cell internalization, making them inefficient in delivering drugs to cells. Protein-resistant yet cell membrane-binding polymers will simultaneously achieve long blood circulation and fast cellular internalization, but their designs are generally complicated, such as introducing cell-membrane binding groups. Here, it is shown that the N-alkyl chain length of zwitterionic poly(sulfobetaine) can be used to tune its affinity toward proteins and cell membranes. A poly(sulfobetaine) with a moderately long N-alkyl chain became cell membrane-philic while retaining protein resistance, leading to long blood circulation and fast cellular uptake, which further triggered efficient tumor cell transcytosis and intratumor penetration. Thus, its paclitaxel (PTX)-loaded micelles demonstrated potent antitumor efficacy in triple-negative breast cancer models. This study showcases a paradigm of designing polyzwitterions harmonizing long blood circulation and fast cellular uptake properties as tumor-active drug delivery carriers.