In vivo tumor gene delivery using novel peptideticles: pH‐responsive and ligand targeted core–shell nanoassembly

Modulating cancer causing genes with nucleic acid based‐molecules as cutting‐edge approaches need efficient delivery systems to succeed in clinic. Herein, we report design and fabrication of a novel tissue penetrating peptideticle with charge‐structure switching in tumor microenvironment for an effective gene delivery. The comparative in vitro studies indicate that peptideticles identify and bind to tumor endothelial cells and efficiently penetrate into multicellular tumor spheroid. In addition, negatively charged peptideticle at pH 7.4, prevent unwanted interaction while its sharp charge‐structure switching at pH 6.2–6.9 (e.g. in tumor tissue) facilitates malignant cells penetration. More importantly, upon systemic administration into tumor bearing mice, peptideticles effectively localized in tumor tissue and delivered luciferase gene with a 200‐fold higher efficiency compared to their non‐pH‐responsive counterparts. In conclusion, this study presents a robust nanoassembly of safe materials for high efficient tumor gene delivery. What's new? Nucleic acid‐based drugs can be designed to specifically silence oncogenes or to restore tumor suppressor gene expression. The functional delivery of RNA/DNA‐based drugs, however, remains a challenge. Here, the authors genetically tailored peptide‐based nanoparticles, generating so‐called “peptideticles,” that effectively identified tumor vasculatures and penetrated tumor microenvironments for gene delivery in tumor‐bearing mice. Peptideticles embedded into HNH peptides successfully escaped intracellular barriers and showed enhanced intracellular gene delivery rate. A pH‐responsive shell covering the exterior of HNH peptideticles further improved blood circulation half‐life and reduced nonspecific interactions. The findings open new avenues for improving nucleic acid drug delivery to tumor tissues.