Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly (lactic-co-glycolic acid)(PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10 EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10 EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10 EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10 EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors.