Large-Mesopore Covalent Organic Framework Nanoparticles for Small Interfering RNA Delivery toward Cancer Immunotherapy

Abstract Small interfering RNA (siRNA) offers a promising modality for tumor immunotherapy through a precise gene-silencing mechanism, whereas its efficient loading and in vivo delivery rely on specialized carriers because of its polyanionic nature. Porous nanomaterials represent attractive platforms for designing such carriers. However, constructing biocompatible porous organic materials for efficient siRNA loading and in vivo delivery is challenging because structurally stable organic nanoparticles (NPs) with abundant, ordered, and large mesopores have rarely been reported. Herein, a linker-design strategy that balances rigidity and flexibility was used to synthesize covalent organic frameworks (COFs), resolving the dilemma of simultaneously producing organic NPs and preserving ordered large mesopores. Specifically, grafting flexible allyloxy chains onto rigid, poorly soluble linkers enhanced linker solubility and interlayer interactions, enabling the synthesis of a series of mesoporous COF nanoparticles. Thereinto, 4,4′-(1,2-ethynediyl)bis(2-allyloxybenzaldehyde) and 1,3,5-tris(4-aminophenyl)benzene-derived COF (TECOF) NPs exhibited a mesopore aperture of 4.5 nm, which, to the best of our knowledge, is the largest reported for COF nanoparticles to date. Subsequently, TECOF NPs were applied as platforms to covalently graft a cisplatin-COOH complex (Pt(IV)) and encapsulate a model siRNA (siPDL1) to generate siPDL1@TECOF-Pt. After tumor-cell uptake, grafted Pt(IV) was proven to induce pyroptosis, while channel-loaded siPDL1 was released to silence PD-L1 expression. Such a nanoscale-mesoporous-COF-assisted immunotherapy strategy demonstrated significant tumor growth inhibition and prolonged survival in 4T1 tumor-bearing mice. This study provides a proof-of-concept for the construction of large-mesopore COF NPs for efficient siRNA loading and in vivo delivery.