Hydrogen
peroxide (H2O2)-generating enzymes (HGEs) are
potentially useful for tumor therapy, but the potential is limited
by the challenge in regulating H2O2 production.
Herein, we present site-specific in situ growth of a cationic polymer
poly(N,N′-dimethylamino-2-ethyl
methacrylate) (PDMA) from the N-terminus of glucose oxidase (GOX)
to generate a site-specific and cationic GOX–PDMA conjugate
with well-retained activity and enhanced stability to regulate H2O2 generation for cancer starvation and H2O2 therapy. Notably, the efficiency of endocytosis of
the conjugate was 4-fold higher than that of free GOX. As a result,
relative to free GOX, the conjugate showed 1.5-fold increased cytotoxicity,
2-fold enhanced tumor retention, and 5-fold increased tolerability
after intratumoral injection. Importantly, a single intratumoral injection
of the conjugate completely abolished colon tumors without detectable
side effects, whereas free GOX was ineffective and systemically toxic.
This chemistry may provide a new, simple, general, and efficient solution
to regulate H2O2 production and thereby to dramatically
improve the antitumor efficacy of HGEs while reducing side effects.