Biochemical Structure Evolved Pyridine-Activated Carbon Dots Co-Assembly as Precision Antitumor Nanozyme

Nanozymes with stable activity and excellent biocompatibility hold significant potential for tumor catalytic therapy. However, lacking rational structure evolution strategies to enhance nanozyme biochemical activity and their almost non-tumor specificity have hindered their clinical translation. In this study, we report a pyridine-activated donor-acceptor (D-A)-typed carbon dots (N-CDs), and their co-assembled nanoplatform (N-CDs@KK) with a programmed death-ligand 1 (PD-L1) targeting peptide (KK), as a potent tumor-targeted nanozyme. N-CDs were engineered through structure evolution via homogeneously integrating electron-withdrawing pyridine units into amino-rich conjugated sp²-domains, leading to effective charge transfer. The resulting D-A-typed N-CDs with abundant polarized domains garnered effective adsorption and activation sites, which exhibited both peroxidase (POD)- and oxidase (OXD)-like catalytic activities. Moreover, this elaborate pyridine-activated D-A nanostructure endowed bio-regulatory function, capable of suppressing PI3K/AKT antioxidant stress pathway, thus amplifying reactive oxygen species (ROS)-mediated tumor killing effect. Furthermore, co-assembling with KK, the resulting N-CDs@KK showed enhanced tumor targeting capability with specific cellular internalization. Combining ROS-mediated immunogenic cell death (ICD) and PD-L1 immune checkpoint inhibition (ICI), N-CDs@KK demonstrated to be an efficient tumor-targeted nanoplatform for both nanozyme-catalytic and immunotherapeutic antitumor therapy. We prospect that N-CDs@KK development establishes a paradigm for the rational design of high-performance nanozymes, paving the way for precision nanozyme-based antitumor therapy.