Surface engineering with pH-responsive polyserotonin and self-activated DNAzyme for better microbial therapy of tumor.

Bacteria-based microbial immunotherapy shows various unique properties for tumor therapy owing to their active tropism to tumor and multiple anti-tumor mechanisms. However, its clinical benefit is far from satisfactory, which is limited by rapid systemic clearance and neutrophils-mediated immune restriction to compromise the efficacy, as well as non-specific distribution to cause toxicity. To address all these limitations, herein we reported a polyserotonin (PST) coated () with surface adsorption of DNAzyme (Dz)-functionalized MnO nanoparticles (DzMN) for tumor therapy. PST could facilely coat on surface via oxidation and self-polymerization of its serotonin monomer, which enabled surface stealth to avoid rapid systemic clearance while maintaining the tumor homing effect. Upon targeting to tumor, the PST was degraded and exfoliated in response to acidic tumor microenvironment, thus liberating to recover its anti-tumor activities. Meanwhile, the DzMN was also delivered into tumor via hitchhiking , which could release Dz and Mn after tumor cells internalization. The Dz was then activated by its cofactor of Mn to cleave target PD-L1 mRNA, thus serving as a self-activated system for gene silencing. Combining and Dz for immune activation and PD-L1 knockdown, respectively, anti-tumor immunotherapy was achieved with enhanced efficacy. Notably, PST coating could significantly decrease infection potential and non-specific colonization of at normal organs, achieving high in vivo biosafety. This work addresses the key limitations of for in vivo application via biomaterials modification, and provides a promising platform for better microbial immunotherapy.