Polypeptide nanoparticles: a clinically validated, versatile delivery platform for RNA therapeutics
Nucleic Acid Insights 2026; 3(4), 243–261
DOI: 10.18609/nai.2026.032
RNA therapeutics, including small interfering RNA (siRNA) and messenger RNA (mRNA), have emerged as a transformative class of precision medicines for the treatment of a broad spectrum of pathological conditions, spanning malignant neoplasms, neurodegenerative disorders, and genetic diseases. However, their clinical translation is severely impeded by inherent delivery bottlenecks, most notably the poor in vivo stability of nucleic acids, inefficient cellular uptake, and the inability to selectively target non‑hepatic tissues or traverse the blood–brain barrier (BBB) to access the central nervous system (CNS). Polypeptide nanoparticles (PNP), engineered from biocompatible histidine‑lysine polypeptide (HKP) backbones, have emerged as a promising non‑viral delivery alternative to lipid nanoparticles (LNP), with well‑validated efficacy in siRNA delivery to human cutaneous and adipose tissues in Phase 1/2 clinical trials. This review presents a rigorous, evidence‑based analysis of PNP’s structural design principles, mechanistic underpinnings of nucleic acid delivery, and clinical translational progress. We further elaborate on PNP’s expanded therapeutic potential for tissue‑specific delivery to muscle, ocular, solid tumor, and CNS tissues, and conduct a critical comparative analysis of PNP against other mainstream non‑viral RNA delivery systems (LNP, polymeric nanoparticles, GalNAc‑conjugated siRNA). Additionally, we identify current challenges in PNP development and outline rational, forward‑looking research directions to address these limitations. By integrating quantitative preclinical and clinical data, and contextualizing PNP within the broader landscape of RNA therapeutics, this review establishes PNP as a complementary, versatile delivery platform that addresses unmet clinical needs in non‑hepatic, local, and precision RNA delivery, and positions it as a key enabler for advancing the next generation of RNA‑based therapies.