MOFs‐Based Nanoinducer Enables Excessive Autophagy for Synergistic Photoimmunotherapy

Abstract A core‐shell type of nanoinducer (UCBH) capable of eliciting robust immunogenic cell death based on near‐infrared (NIR) light‐triggered excessive autophagy is developed via the growth of a Cu(II)‐based metal‐organic frameworks (MOFs) shell around the upconversion nanoparticle (UCNP) core with N,N′‐di‐sec‐butyl‐N,N′‐dinitroso‐1,4‐phenylenediamine (BNN6), a type of nitric oxide (NO) precursor, encapsulated within the cavities. Based on the upconverting ability of UCNP, NIR light mediates the Cu(II)‐to‐Cu(I) photoreduction in MOFs and the activation of BNN6, which enables the release of free Cu⁺, the organic ligand 1,3,5‐benzenetricarboxylate (BTC), and NO. Cu⁺ ion mediates the activation of ULK1 and therefore directly initiates autophagy, which is efficiently sustained based on the sufficient supply of autophagy substrates that NO mediates by inducing mitochondrial damage. Additionally, BTC with inherent ability of inducing protein deacetylation plays its role in terms of amplifying the autophagic cascade via the manner of activating ULK1 and impairing mitochondrial metabolism, respectively. Preliminary in vivo evaluation results acquired from the cell‐derived tumor xenograft model unequivocally demonstrate the remarkable therapeutic efficacy of UCBH in inhibiting tumor growth upon irradiation of NIR light, indicating the potential of UCBH as a platform for synergistic photoimmunotherapy with spatiotemporal precision.