Autophagic Cell Survival-to-Death Switch Induced by Cisplatin and Zn(II) Dual-Loaded Dispersity-Tunable Zwitterionic Hybrid Polyion Nanocomplex

Engineered nanomaterials, with their tunable size and surface characteristics, have played a pivotal role in biomedical delivery systems by modulating specific cellular processes such as autophagy and apoptosis, thereby influencing cellular homeostasis and cytotoxicity. Recently, zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) has gained attention for its enhanced biocompatibility and antifouling properties, presenting potential as a promising alternative to poly(ethylene glycol) (PEG) in various biomedical applications. This study investigates the relationship between metal-chelated nanomaterial structures and their biochemical activity using core–corona nanoparticles (NPs) composed of a metallic pharmacophore core and a zwitterionic PMPC polymer shell. Two NP systems were designed, both containing aquated cisplatin ( cis -[Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ ) and a Zn(II) adjuvant, with identical surface structures but contrasting core stabilities, leading to distinct drug release profiles: (1) labile NPs with pH-responsive drug release and variable size dispersity under endosomal conditions and (2) inert NPs characterized by slow drug release and low dispersity due to stable heterometallic Lewis complex formation at the core. The labile NP combinations exhibited strong drug synergism in cytotoxicity through apoptosis and ferroptosis, with cisplatin driving the primary pharmacological effects, while Zn-NPs modulated prosurvival autophagy toward autophagic cell death, which demonstrated the potential of Zn-NPs as a synergistic adjuvant in cisplatin delivery. In contrast, Pt/Zn-coloaded inert NPs exhibited controlled drug release and cytotoxicity, showing approximately 8–11 times higher IC 50 values than those of labile NP combinations, depending on the combination ratio. These results demonstrate the critical role of the NP structure in modulating cytotoxicity and autophagy, providing insights for the rational design of effective drug delivery systems.