Designer Anticancer Nanoprodrugs with Self‐Toxification Activity Realized by Acid‐triggered Biodegradation and In Situ Fragment Complexation

Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a “degradation‐mediated self‐toxification” strategy, which realizes intracellular synthesis of anticancer agents using the nanoparticles’ own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH) 2 nanodots confined hollow silica nanospheres (PD‐HSN). This constructed nanoprodrug shows acid‐triggered degradation in lysosomes and neutralizes protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd 2+ and DCP‐silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.