Virus-inspired lipopeptide vectors achieve dual-entry macromolecule delivery and deep tumor penetration.

The clinical translation of biomacromolecular drugs, including nucleic acids and proteins, is severely hampered by their poor bioavailability. These large molecules often face rapid degradation, inefficient cellular uptake, and significant barriers to tissue penetration, particularly in dense or poorly permeable tissues like tumors. Current delivery strategies frequently fall short, struggling to navigate physiological and pathological obstacles. This creates a critical gap in therapeutic efficacy, as many promising biologics cannot reach their intracellular targets effectively or achieve sufficient concentrations within diseased tissues, necessitating innovative delivery platforms.

Researchers developed virus-inspired enveloped lipopeptide vectors designed to mimic natural viral envelopes. These vectors integrate two complementary entry mechanisms: hyaluronic acid-guided, receptor-mediated endocytosis and tumor microenvironment-activated membrane penetration. The latter mechanism involves the exposure of an arginine-rich corona in response to specific tumor stimuli. The team evaluated the vectors' versatility for encapsulating diverse biomacromolecules, including nucleic acids, proteins, and supramolecular assemblies, and assessed their efficiency in intracellular delivery, transcytosis, and intercellular transfer to enhance deep tumor penetration.

The virus-inspired enveloped lipopeptide vectors demonstrated remarkable versatility, successfully encapsulating a wide range of biomacromolecules, from nucleic acids to proteins and complex supramolecular assemblies. They achieved efficient intracellular delivery across various cell types. A key finding was the vectors' ability to facilitate transcytosis and subsequent intercellular transfer, which is crucial for overcoming tissue barriers. This dual-entry strategy, combining receptor-mediated endocytosis and tumor microenvironment-activated direct membrane penetration, significantly enhanced deep tumor penetration. The system effectively recapitulates key principles of viral infection in a synthetic, programmable platform.

This dual-entry strategy, combined with transcytosis-enabled intercellular transfer, enables deep tumor penetration and efficient intracellular delivery of diverse biomacromolecules.