Abstract
Peptide-drug conjugates (PDCs) represent an emerging class of targeted therapeutics engineered to enhance drug specificity and minimize systemic toxicity, showing significant promise for treating complex diseases. The peptide component is central to this strategy, fulfilling multiple critical roles. Primarily, it acts as a high-affinity homing device, selectively directing the conjugate to receptors overexpressed on target cells to minimize off-target effects. Beyond targeting, peptides are also being innovatively engineered as enzymatically cleavable linkers to enable selective drug release within a specific pathological microenvironment. Despite this potential, the clinical translation of PDCs is hindered by challenges including instability in circulation, limited tissue penetration, and insufficient targeting selectivity. This review discusses strategic advances in peptide discovery, modification, and optimization to overcome these barriers. We further provide future perspectives on constructing next-generation PDCs, underscoring their potential as highly effective precision medicines.