G₄-Hemin-loaded 2D nanosheets for combined and targeted chemo-photodynamic cancer therapy

Synergetic combination therapy is emerging as one of the most promising approaches for cancer treatment. Among the various therapeutic approaches, PDT has received particular attention due to its non-invasive nature. However, the therapeutic performance of PDT is severely affected by tumour hypoxia. Herein, we report a supramolecular strategy for the fabrication of a PDT-active 2D nanosheet loaded with a POD mimicking DNAzyme for the synergetic combination of PDT and CDT for targeted cancer therapy. Assembly of biotin-functionalized BODIPY (1) and cationic β-cyclodextrin (β-CD+) leads to the formation of a 1/β-CD+ nanosheet with positively charged β-CD+ on the surface of the sheet. The cationic face of the 1/β-CD+ sheet was then loaded with a POD-mimicking Hem-loaded G-quadruplex aptamer (Hem/DNA1) via electrostatic interactions (1/β-CD+/Hem/DNA1). Cellular internalization of the 1/β-CD+/Hem/DNA1 nanosheet occurs via a receptor-mediated endocytic pathway, which then undergoes lysosomal escape. Subsequently, Hem/DNA1 on the surface of 1/β-CD+/Hem/DNA1 reacts with endogenous H₂O₂via the Fenton pathway to produce ˙OH and O₂. Moreover, under cellular conditions, Hem inside the 1/β-CD+/Hem/DNA1 nanosheet produces Fe²⁺, which then undergoes another Fenton reaction to produce ˙OH and O₂. The Fe³⁺ generated after the Fenton reaction is then reduced in situ to Fe²⁺ by glutathione for the next Fenton cycle. At the same time, photoirradiation of the 1/β-CD+ nanosheet using a 635 nm laser produces ¹O₂via the PDT pathway by using endogenous O₂. The most remarkable feature of the present nanoformulation is the cooperativity in its therapeutic action, wherein O₂ produced during the CDT pathway was used by the 1/β-CD+ sheet for improving its PDT efficacy in the hypoxic tumor microenvironment. This work represents a unique combination of CDT and PDT for targeted cancer therapy, wherein the CDT action of the nanoagent enhances the PDT efficacy and we strongly believe that this approach would encourage researchers to design similar combination therapy for advancements in the treatment of cancer.