A Self-Therapeutic Upconversion Polyphenolic Nanoreactor for NIR-Assisted Multifaceted ROS Generation and Dual...

Conventional chemotherapy with drug-loaded hybrid nanosystems is restricted by limited drug delivery, poor loading content, internal accumulation, or premature drug release. Drug-derived nanoreactors acting as self-therapeutic agents are considered a promising approach to address these challenges. Herein, we report a curcumin-loaded copper-quercetin self-assembled upconversion nanocomposite (UCuQ@Cur) to achieve NIR-mediated PDT/CDT/chemotherapy. The cationic NaYF4:Yb,Tm (UCNPs) allowed electrostatic association of quercetin, followed by Cu2+ chelation to yield a Cu-quercetin shell on UCNPs (UCuQ) through a rapid in situ method under room temperature. UCuQ@Cur effectively addressed the challenges of water insolubility and internal accumulation of pure quercetin. Subsequently, the porous structures of UCuQ allowed substantial curcumin loading, thus altering the visible-range (400-500 nm) excitation of curcumin to NIR (980 nm) range. DFT investigations illustrated divalent coordination of a Cu2+ ion with two quercetin molecules in square-planar geometry, exhibiting the highest stability with a band gap of 94.19 kcal/mol. MD simulations established strong electrostatic coordination of curcumin with UCuQ. The complex heterogeneity of tumor microenvironment (TME) exhibits elevated GSH, drug resistance, and low oxygen, making monotherapy inadequate. UCuQ@Cur utilizes these conditions to act as a self-mediated chemotherapeutic system integrating oxidative stress-induced treatment. Once internalized, UCuQ@Cur facilitated Förster Resonance Energy Transfer (FRET) between UCNP and curcumin to generate (1O2) under 980 nm laser. Acidic pH of tumor promoted sustained release of quercetin and curcumin, exhibiting dual chemotherapy. The released Cu2+ ions are reduced into Cu+ by intracellular GSH, which reacts with H2O2 to produce (•OH) through Fenton reaction. The polyphenolic drug-derived multimodal nanoreactor exhibits remarkable stability, biocompatibility, and significant cellular apoptosis (IC50 value: 5.79 μg/mL) against cancer cells. In vitro performance of the composites against the HeLa tumor spheroid model, intracellular ROS generation, and Calcein-AM/EthD-III-stained apoptosis assay confirmed efficient therapeutic activity.