Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands the reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs and delves into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems.

Therapeutic protein, represented by antibodies, is of increasing interest in human medicine. However, clinical translation of therapeutic protein is still largely hindered by different aspects of developability, including affinity and selectivity, stability and aggregation prevention, solubility and viscosity reduction, and deimmunization. Conventional optimization of the developability with widely used methods, like display technologies and library screening approaches, is a time and cost-intensive endeavor, and the efficiency in finding suitable solutions is still not enough to meet clinical needs. In recent years, the accelerated advancement of computational methodologies has ushered in a transformative era in the field of therapeutic protein design. Owing to their remarkable capabilities in feature extraction and modeling, the integration of cutting-edge computational strategies with conventional techniques presents a promising avenue to accelerate the progression of therapeutic protein design and optimization toward clinical implementation. Here, we compared the differences between therapeutic protein and small molecules in developability and provided an overview of the computational approaches applicable to the design or optimization of therapeutic protein in several developability issues.

Nanoparticles (NPs) are usually treated as multifunctional agents combining several therapeutical applications, like imaging and targeting delivery. However, clinical translation is still largely hindered by several factors, and the rapidly formed protein corona on the surface of NPs is one of them. The formation of protein corona is complicated and irreversible in the biological environment, and protein corona will redefine the “biological identity” of NPs, which will alter the following biological events and therapeutic efficacy. Current understanding of protein corona is still limited and incomplete, and in many cases, protein corona has adverse impacts on nanomedicine, for instance, losing targeting ability, activating the immune response, and rapid clearance. Due to the considerable role of protein corona in NPs’ biological fate, harnessing protein corona to achieve some therapeutic effects through various methods like biomimetic approaches is now treated as a promising way to meet the current challenges in nanomedicine such as poor pharmacokinetic properties, off-target effect, and immunogenicity. This review will first introduce the current understanding of protein corona and summarize the investigation process and technologies. Second, the strategies of harnessing protein corona with biomimetic approaches for nanomedicine design are reviewed. Finally, we discuss the challenges and future outlooks of biomimetic approaches to tune protein corona in nanomedicine.

Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands a reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs, delve into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems.

Melittin is a membrane-active peptide with strong anticancer activity against various cancers. Despite decades of research, the role of the singular Trp in the anticancer activity and selectivity of melittin remains poorly understood. Here, we propose a theranostic solution based on the substitution of Trp19 with a noncanonical fluorescent amino acid (Dap^AMCA). The introduction of Dap^AMCA residue in melittin stabilized the helical structure of the peptide, as evaluated by circular dichroism spectra and molecular dynamics simulations. In vitro hemolytic and anticancer activity assays revealed that introducing Dap^AMCA residue in melittin changed its mode of action with the cell membrane, resulting in reduced hemolytic toxicity and an improved the selectivity index (SI), with up to a five-fold increase compared to melittin. In vitro fluorescence imaging of Dap^AMCA-labeled melittin (MEL^FL) in cancer cells demonstrated high membrane-penetrating activity, with strong nuclear and nucleolar localization ability. These findings provide implications for novel anticancer therapies based on Trp-substituted designs and nuclear/nucleolar targeted therapy.