Bioinspired synthetic strategies for enhanced cell membrane interactions for targeted delivery of biomacromolecules.

INTRODUCTION: Biomacromolecular therapeutics, including proteins and nucleic acids, offer high specificity but face major delivery challenges of stability, cellular uptake, and intracellular trafficking. Synthetic bioinspired strategies, ranging from systems that borrow broad principles from nature to biomimetic carriers that closely imitate biological mechanisms, are increasingly being explored to overcome these barriers. AREAS COVERED: This review examines lipid- and polymer-based systems for protein and nucleic-acid delivery, drawn from two paradigms: virus-mimicking systems and peptide/protein pathway-based mimicry. Virus-mimicking platforms are divided into two groups: structural mimicry (capsid-like nanoparticles, fusogenic liposomes, dendrimers) and functional mimicry (pH-responsive endosomolytic and environmentally triggered systems). Pathway-based approaches span receptor-mediated blood-brain barrier transport, fibrinogen bridging for thrombus targeting, and charge-mediated membrane penetration. Relevant literature was identified through PubMed, Nature, Scopus and Web of Science, focusing on the last 15 years of innovation. Unlike reviews centered on membrane-coated biomimetic carriers or on a single modality or barrier, it uses the cell-membrane interaction as a unifying organizing principle across delivery of both cargo types. EXPERT OPINION: Computational design, machine-learning-guided optimization and hybrid lipid - polymer architectures are expected to accelerate translation, while stimuli-responsive, multifunctional nanoparticles integrating targeting, controlled release and diagnostics will likely define the next generation of precision biomacromolecule delivery systems.