Shibyendu Nikhar, Afshan Jahan, Tumpa Mahato, Ardhendu Sekhar Giri
Active targeting has emerged as a critical design strategy in precision nanomedicine, enabling nanocarriers to overcome biological barriers and achieve selective accumulation at disease sites. Peptides and antibodies represent complementary targeting ligands that can be combined to develop high-performance contrast agents and drug delivery systems. This review provides mechanistic analysis of nanoparticles (NPs) functionalized with peptides and antibodies, examining how ligand chemistry, receptor affinity, and surface engineering enhance biological selectivity, intracellular transport, and therapeutic efficacy. We discuss three major classes of targeting peptides─tumor-homing, cell-penetrating, and receptor-binding sequences─alongside monoclonal antibodies, single-chain fragments, and Fab derivatives, emphasizing their distinct roles in molecular recognition, endocytic pathways, and biodistribution. The review covers key bioconjugation strategies including maleimide–thiol ligation, EDC/NHS [1-ethyl-3-(3-(dimethylamino)propyl carbodiimide/ N -hydroxysuccinimide] coupling, click chemistry, and bio-orthogonal methods that enable site-specific conjugation suitable for clinical translation. Applications in MRI, CT, and fluorescence imaging demonstrate how peptide- or antibody-targeted nanoparticles improve image contrast and enable early detection of cancer and neurological disorders. Also, targeted drug-delivery platforms employ ligand-mediated accumulation, improve barrier penetration, and allow stimulus-responsive release. The integration of peptide penetration and antibody affinity in dual-ligand designs overcome tumor heterogeneity, enabling theranostic platforms that integrate imaging and therapy with reduced off-target effects.