Self-boosting targeted anticancer therapy <i>via</i> cancer cell self-reprogramming with GGT-targeting oxidative stress nanoamplifiers

<b>Rationale:</b> <i>Gamma</i>-glutamyl transferase (GGT) is overexpressed on cancer cell membranes and has been widely used as a promising target for receptor-mediated therapy. However, its heterogeneous expression limits targeting efficacy. Based on the notation that reactive oxygen species (ROS) upregulate GGT and induce oxidative stress-mediated cancer cell death, we hypothesized that GGT-targeted ROS generation could simultaneously induce cell death and also reprogram tumors to achieve self-boosting targeted therapy. <b>Methods:</b> We developed GLOXmp, a glutamic acid (Glu)-coated oxidative stress nanoamplifier, in which glutathione (GSH)-depleting B2C was loaded in ROS-generating amphiphilic polyCA. GLOXmp was designed to induce oxidative stress, modulate GGT expression, subsequently enhancing tumor targeting both in vitro and in vivo using xenograft mouse models. <b>Results:</b> GLOXmp internalized GGT-overexpressing cancer cells and concurrently generated ROS and depleted intracellular GSH, leading to mitochondrial damage and potent cancer cell death. Importantly, GLOXmp reprogrammed tumor cells to upregulate GGT, leading to the enhancement of receptor-mediated uptake of subsequent doses. In tumor xenograft model, repeated administration of GLOXmp significantly elevated oxidative stress, increased GGT expression, and effectively eradicated tumors without systemic toxicity. <b>Conclusion:</b> GLOXmp specifically targeted GGT-overexpressing cancer cells and effectively suppressed tumor development through oxidative stress amplification. Given a self-reinforcing strategy for targeted cancer therapy through oxidative stress-mediated tumor cell reprogramming, GLOXmp demonstrates represents a promising advancement in precision nanomedicine.