Peptide core spherical nucleic acids circumvent tumor immunosuppression via supplementing methionine for enhanced photodynamic/gene immune/therapy of hepatocellular carcinoma

Spherical nucleic acids (SNAs) with functional peptide cores are an emerging nanoplatform for synergistic cancer therapy but have been rarely reported. We construct herein the first SNA nanoplatform based on a biodegradable binary peptide backbone of methionine (Met) and cysteine (Cys) for codelivery of a photosensitizer, Chlorin e6 (Ce6) and human liver-specific miR122 for synergistic photodynamic-gene therapy of hepatic cell carcinoma (HCC). Met supplementation by the peptide core improves the infiltration of T cells and enhances the effector function of T cells for turning a “cold” tumor into a “hot” one. The resulting SNA(+) shows the most significant inhibitory effect in a Hepa1-6 HCC primary/distal tumor model, with tumor growth inhibition (TGI) values of 98.5 ± 0.5 % and 99.1 ± 0.4 % for the primary and distant tumors, respectively. This SNA nanoplatform achieves superior high TGI values reported thus far to our knowledge with almost complete eradication for both tumors due to the simultaneous adaptive and innate immunity activation via photodynamic therapy (PDT) induced immunogenic cell death (ICD) and Met supplementation-promoted adaptive immunity, and miR122-enhanced innate immunity. Overall, this study not only develops a reliable synthetic strategy toward peptide-backboned multifunctional SNA nanoplatform, but also reports the modulation of amino acid metabolism for enhanced innate immunity for highly efficient HCC immunotherapy.