Tumor-associated miRNAs activated HCR-DNAzyme theranostic nanosystem to trigger innate- and adaptive-immune responses for long-term immunotherapy

•Detailly present that dsDNA formed by HCR activates the cGAS-STING signaling.•miRNA-triggered controllable DNAzyme is designed for gene silencing of PD-L1.•H/LDz-M@B simultaneously realize innate and adaptive antitumor immunotherapy.•H/LDz-M@B theranostic nanosystem has both tumor imaging and therapy functions. Targeted manipulation of cytoplasmic double-strand (dsDNA) generation in tumors to activate cGAS-STING signaling remains challenging in antitumor immunity. Herein, we proposed an endogenous tumor-associated microRNAs-triggered theranostic nanosystem for codelivery of Hybridization Chain Reaction (HCR) and DNAzyme systems to achieve robust long-term antitumor immunity based on MnO2-adjuvant nanoparticles. The MnO2 was decomposed into Mn2+ ions in the endosome and thus released HCR and DNAzyme systems. Endogenous miR-21-triggered HCR for dsDNA generation, thereby resulting in cGAS-STING signaling activation. Meanwhile, the DNAzyme system was unlocked and catalyzed respectively via endogenous miR-146a and cofactor Mn2+ ions for gene silencing of programmed cell death ligand 1 (PD-L1) to achieve immune-checkpoint blockade (ICB). The combination of innate immunity based on HCR system and adaptive immune-responses mediated by DNAzyme system acquired robust antitumor immunity and long-term immune effect on distal tumors and pulmonary metastasis in vivo. In summary, this endogenously-responsive nanosystem with self-supplied cytoplasmic dsDNA presents strong antitumor immune activation and provides a long-term immunotherapeutic potential for cancer therapy.