The application of nanotechnology for in medicine is developing rapidly, thereby increasing human exposure to nanomaterials and significantly so. A rising question is the biosecurity of nanoparticles (NPs). Although calcium phosphate (CaP) phase is biocompatible and biodegradable, many in vitro experiments have demonstrated that its NPs have significant cytotoxicity. This toxicity is due to that the released Ca²⁺ ions from the internalized CaP NPs within cells initiate apoptosis. Different from such an understanding, we reveal that the internalized CaP NPs actually result in lysosomal ruptures caused by the fast dissolution of CaP under acidic conditions. The suddenly released ions disturb the osmotic pressure balance across the lysosomal membranes destroying the lysosomes, and excessive lysosomal ruptures lead to cell necrosis. We find that the necrosis process can be regulated by intracellular environments. For examples, the lysosomal ruptures can be inhibited by increasing either cytoplasmic osmotic pressure or lysosomal pH (reduce the dissolution rates of CaP). These changes can significantly decrease the cytotoxicity of CaP NPs. It follows that lysosomal rupture prevention is important in the biomedical applications of CaP NPs. More generally, the study suggests that control of material degradation in lysosomes and cytoplasm osmotic pressure may improve the biosecurity of nanomaterials, which is of special importance to biomimetic nanomaterials.