A Metformin-Based Multifunctional Nanoplatform as a DNA Damage Amplifier for Maximized Radio-Immunotherapy to Overcome Radiotherapy Resistance

Radiotherapy (RT) has been highlighted to be an effective strategy for antitumor immunity activation by causing direct DNA damages, but it generally suffers from low response rates due to the compromised cytosolic DNA (cDNA) recognition by cyclic GMP-AMP synthase (cGAS). Simultaneous DNA repair and clearance system regulation for enhanced cDNA accumulation is a useful approach to improve immune response rates, which remains seldom reported to our knowledge. Here, we report the construction of a metformin (MET)-based multifunctional nanocomplex, CS-MET/siTREX1 (CSMT), consisting of biguanide-decorated CS (CS-MET) as the vector and 3'-5' DNA exonuclease TREX1 siRNA (siTREX1) as the therapeutic gene for RT-induced antitumor immunity enhancement by amplifying the initial DNA damage signals. The uniqueness of this study is the development of CSMT as a specific DNA damage amplifier to promote cDNA accumulation for maximizing radio-immunotherapy and circumventing RT resistance. Specifically, the CSMT nanocomplexes show not only enhanced gene transfection efficiency by MET modification but also synergistic therapeutic effects including MET's inhibition on DNA repair and siTREX1's attenuation on cDNA clearance, which leads to the greatest inhibitory effect in a Hepa1-6 proximal/distal tumor model with a high tumor growth inhibition (TGI) value of 99.1% for the primary tumor and significantly compromised distal tumor growth by inducing immunogenic cell death (ICD), promoting tumor-associated neutrophil (TAN) polarization, and stimulating tumor-specific memory T-cell generation. Overall, the CSMT nanocomplexes developed herein hold great translatable promises for overcoming RT resistance in clinics.