Orthogonal upconversion mimicking Nd-Mn heterometallic nanocomposite for dual NIR responsive self-amplifying photodynamic/chemodynamic therapy.

Shallow tissue penetration of excitation light remains the most persistent barrier to effective photodynamic therapy (PDT), compounded further by tumour hypoxia and elevated glutathione (GSH). Herein, we report a rationally engineered core-shell nanoplatform comprising a Mn-centred porphyrinic metal-organic framework constructed from Nd3+ coordination nodes (MN-MOF) and integrated with NaYbF4:Tm upconversion nanoparticles (UCNPs). The strategic integration of neodymium (Nd) as the Nd-porphyrin MOF contributes towards bandgap modulation and photophysical optimization necessary to achieve FRET derived orthogonality. Consequent activation of discrete luminescent channels within a single nanoparticle using different wavelengths (980 nm/808 nm) of light facilitates cytotoxic singlet oxygen (1O2) generation. The incorporation of Mn into the porphyrinic centre facilitates efficient Mn3+/Mn2+ redox cycling, driving Fenton-like reactions that generate hydroxyl radicals (˙OH) while depleting intracellular GSH, thereby enhancing oxidative stress. Concurrently, Mn catalyses the decomposition of endogenous H2O2 to generate O2, relieving tumour hypoxia and promoting 1O2 generation. Furthermore, lactobionic acid (LA) functionalised UCNP@MN (UMNL) demonstrates ASGPR receptor-mediated selective elimination of hepatic cancer cells (cell death ∼64-70%). Overall, this work provides a novel coordination-driven approach towards near infrared (NIR) light-activated multifunctional nanoplatforms that overcome tumour microenvironment (TME) associated challenges while enhancing the synergistic efficacy of chemodynamic and photodynamic therapy.