Charge regulated pH/NIR dual responsive nanoplatforms centered on cuproptosis for enhanced cancer theranostics

Multifunctional nanoplatforms capable of simultaneously executing multimodal therapy and imaging functions are of great potentials for cancer theranostics. We present an elegantly designed, easy-to-fabricate poly(acrylic acid)/mesoporous calcium phosphate/mesoporous copper phosphate nanosphere (PAA/mCaP/mCuP NS) with outstanding pH/NIR-sensitive multimodal-synergic anti-tumor effects. Optimal porous PAA NS scaffolds were prepared at room temperature by balancing the intra-PAA polymer and polymer-solvents Lennard-Jones potentials in a water:isopropyl alcohol (IPA) mix-solvent. Subsequent sponging of Ca²⁺ and Cu²⁺, and adsorption of PO₄^3- to the PAA template were achieved through exquisite electrostatic interactions among ions and the ionizable PAA side-chain in an aqueous environment. This forms the basis for the tumor microenvironment pH-triggered release of Cu²⁺ to induce cuproptosis, as well as the photothermal effect originating from CuP, while Ca²⁺ can enhance the nanoplatform's biocompatibility and can damage mitochondria when overloaded. Lastly, PAA/mCaP/mCuP NSs still exhibit high drug loading efficiency for doxorubicin (DOX), enabling chemotherapy. Satisfactory anti-tumor effects of these modalities, along with their synergistic effects, were verified both in vitro and in vivo, with the NSs demonstrating good biodegradation in the latter. The fabricated NS itself holds great promise as an anti-tumor nanomedicine, and the thorough mechanical insights into NS formation may inspire the design of next-generation multifunctional nanoplatforms.