Enzymatic Self-Assembly Confers Exceptionally Strong Synergism with NF-κB Targeting for Selective Necroptosis of Cancer Cells.

As a promising molecular process for selectively inhibiting cancer cells without inducing acquired drug resistance, enzyme-instructed self-assembly (EISA) usually requires relatively high dosages. Despite its discovery 30 years ago, the translation of the knowledge about NF-κB signaling into clinic remains complicated due to the broad roles of NF-κB in cellular regulation. Here we show that integrating EISA and NF-κB targeting boosts the efficacy of EISA over an order of magnitude without compromising selectivity against cancer cells. That is, in situ enzymatic self-assembly of a tetrapeptide results in nanofibers, which hardly affect cell viability, but lead to inductive expression of tumor necrosis factor receptor 2 (TNFR2) and decreased expression of three key proteins at the upstream of NF-κB pathway in the cancer cells. Adding the inhibitors targeting NF-κB further decreases the expressions of those upstream proteins, which turns the otherwise innocuous nanofibers to being lethal to the cancer cells,...