Engineering Crystallinity Gradients for Tailored CaO 2 Nanostructures: Enabling Alkalinity-Reinforced Anticancer Activity with Minimized Ca 2+ /H 2 O 2 Production.

CaO 2 nanoparticles (CNPs) can produce toxic Ca 2+ and H 2 O 2 under acidic pH, which accounts for their intrinsic anticancer activity but at the same time raises safety concerns upon systemic exposure. Simultaneously realizing minimized Ca 2+ /H 2 O 2 production and enhanced anticancer activity poses a dilemma. Herein, we introduce a "crystallinity gradient-based selective etching" (CGSE) strategy, which is realized by creating a crystallinity gradient in a CNP formed by self-assembled nanocrystals. The nanocrystals distributed in the outer layer have a higher crystallinity and thus are chemically more robust than those distributed in the inner layer, which can be selectively etched. CGSE not only leads to CNPs with tailored single- and double-shell hollow structures and metal-doped compositions but more surprisingly enables significantly enhanced anticancer activity as well as tumor growth inhibition under limited Ca 2+ /H 2 O 2 production, which is attributed to an alkalinity-reinforced lysosome-dependent cell death pathway.