Enveloped lipopeptide vectors mimic viral dual entry routes via endocytosis and membrane penetration for efficient macromolecule delivery

The therapeutic success of biomacromolecular drugs is fundamentally limited by their poor bioavailability, particularly in hard-to-deliver cells and poorly permeable tissues. To address these challenges, we developed virus-inspired lipopeptide vectors that mimic viral envelopes to enable receptor-mediated endocytosis, and these vectors expose arginine-rich coronas in response to tumor-specific stimuli for direct membrane penetration. The virus-inspired enveloped lipopeptide vectors exhibited remarkable versatility for encapsulating diverse biomacromolecules (including nucleic acids, proteins, and supramolecular assemblies) and achieved efficient intracellular delivery. Furthermore, enveloped lipopeptide vectors facilitated transcytosis and subsequent intercellular transfer, thereby enhancing deep tumor penetration. This work presents a robust virus-inspired delivery platform with enhanced cargo encapsulation and delivery performance, providing a promising strategy to surmount physiological and pathological barriers in biomacromolecule delivery. STATEMENT OF SIGNIFICANCE: Biomacromolecular therapeutics such as nucleic acids and proteins hold great promise, yet their clinical translation is limited by rapid degradation, poor tumor penetration, and inefficient cellular uptake. Inspired by natural enveloped viruses, we developed virus-mimetic enveloped lipopeptide nanoparticles that integrate two complementary entry mechanisms: hyaluronic acid-guided, receptor-mediated endocytosis and tumor microenvironment-activated membrane penetration through exposure of an arginine-rich corona. This dual-entry strategy, combined with transcytosis-enabled intercellular transfer, enables deep tumor penetration and efficient intracellular delivery of diverse biomacromolecules. By recapitulating key principles of viral infection in a synthetic, programmable system, this work establishes a broadly adaptable platform to enhance the bioavailability and therapeutic efficacy of large biologics, offering a new conceptual framework for biomacromolecular drug delivery.