A multichannel Ca2+ nanomodulator amplifies exogenous and endogenous calcium overload for efficient antitumor and antimetastasis therapy

Calcium overload–based antitumor therapy via disruption of Ca2+ homeostasis has attracted significant attention, although the efficient elevation of calcium overload is extremely challenging. We designed an exogenous and endogenous Ca2+ multichannel nanomodulator (Lipo CaO2–TA–Fe3+/PArg). The material comprises tannic acid (TA) and Fe3+ assembled with calcium peroxide (CaO2) (CaO2–TA–Fe3+) and polyarginine (PArg) incorporated into a pH-responsive liposome. Upon internalization by the tumor cell, lysosomal acidity triggers TA and Fe3+ dissociation, stimulating CaO2 disintegration to self-supply Ca2+ and hydrogen peroxide (H2O2). The dissociated TA reduced Fe3+ to Fe2+, which reacted with H2O2 by the Fenton reaction, yielding self-circulating oxidative hydroxyl radicals (•OH). Most important, •OH oxidizes PArg for sustained nitric oxide (NO) production. The Lipo CaO2–TA–Fe3+/PArg nanomodulator amplified calcium overload via multiple channels: self-supplied exogenous Ca2+, •OH-opened Ca2+ influx channel (TRPA1), and closed outflux pump (PMCA4), and NO opened the ryanodine receptors (RyRs) on endoplasmic reticulum (ER) calcium stores. Amplification of calcium overload activated mitochondrial-mediated apoptosis pathways and resulted in 81.33% tumor inhibition in vivo. It also induced Calpain1 protease-inhibited depolymerization of action cytoskeleton, thereby inhibiting tumor metastasis. This exogenous and endogenous multichannel Ca2+ nanomodulator amplifies calcium overload and holds great promise for efficient ion interference-based antitumor and anti-metastasis therapy.