Peptide-Drug Conjugates for Targeted Delivery in Hematological Malignancies: From Design Principles to Clinical Application.

Hematological malignancies account for over 1.3 million new cases and approximately 700,000 deaths annually. Despite advances in targeted therapies, immunotherapies, and antibody-drug conjugates, relapse, refractory disease, and acquired drug resistance remain critical challenges. Peptide-drug conjugates (PDCs) have emerged as a promising targeted delivery platform, combining peptide-mediated specificity with potent cytotoxic payloads. In this review, we summarized the fundamental design principles of PDCs, including targeting peptide selection, linker engineering, and payload optimization, with emphasis on the biological characteristics of hematological malignancies. We then examined current preclinical and clinical progress across multiple myeloma, acute myeloid leukemia, myelodysplastic syndromes, B-cell non-Hodgkin lymphoma, and chronic myeloid leukemia. We further discussed emerging strategies such as cathepsin B-responsive PROTAC-PDC hybrids, nanotechnology-assisted delivery, and artificial intelligence-guided molecular design. Finally, we addressed key translational challenges, including tumor heterogeneity, payload resistance, and pharmacokinetic constraints, and proposed future directions toward biomarker-driven precision PDC therapy for hematological malignancies.