Peptide–drug conjugates (PDCs) have rapidly gained traction as one of the most dynamic therapeutic platforms in recent years. The 2025 review on PDCs by Wang, Xu, and Yi provides a particularly thorough and timely evaluation of the field. The authors examine PDCs through the lenses of molecular design, mechanism of action, and translational potential, offering a clear snapshot of current progress while articulating where innovation is likely to unfold as PDCs mature beyond early proof-of-concept studies.

The review opens by breaking down the essential architecture of PDCs—a targeting peptide, a linker, and a bioactive payload. The modularity of each element is what makes PDCs especially compelling. Targeting peptides can be derived from diverse homing sequences, including receptor-binding motifs, tumor-penetrating peptides, and cell-penetrating peptides, all of which can be engineered for improved affinity, selectivity, and serum stability. The authors highlight how emerging discovery platforms, such as in vivo phage display, mRNA display, and structure-guided computational design, have accelerated the identification of peptides that selectively recognize receptors overexpressed in tumors or diseased tissues.

Linker chemistry represents another area of significant innovation. The expanding library of cleavable (acid-sensitive, enzyme-responsive, and reduction-sensitive) and non-cleavable linkers enables finely tuned control over when and where payloads are released. Balancing linker stability in circulation with efficient intracellular release remains a central optimization challenge.

Payload diversity is also increasing. While many PDCs still rely on established cytotoxic agents familiar from antibody–drug conjugate (ADC) development, Wang, Xu, and Yi note growing interest in unconventional payloads such as immunomodulators, radionuclides, peptide toxins, and nucleic acids. This shift underscores the broader potential of PDCs as adaptable delivery vehicles for applications extending well beyond oncology.

From a therapeutic perspective, the review emphasizes the advantages of PDCs in cancer—particularly their superior tumor penetration due to their smaller size. At the same time, the field is rapidly expanding into metabolic disease, inflammation, and targeted antimicrobial therapy. Their synthetic accessibility and comparatively reduced manufacturing complexity further elevate PDCs as practical candidates for large-scale clinical development.

Importantly, the authors provide a balanced discussion of ongoing barriers. Peptide instability, rapid clearance, and proteolytic degradation remain persistent hurdles, although strategies such as cyclization, D-amino acid incorporation, PEGylation, and lipidation offer promising improvements. Additional challenges include limited endosomal escape, heterogeneous receptor expression, and the inherent complexity of ADME profiles.

What ultimately makes this review compelling is its framing of PDCs as a credible “next-generation” alternative to antibody–drug conjugates. With advantages in tissue penetration, cost, and manufacturability, PDCs may address several limitations intrinsic to large-molecule biologics. For researchers across peptide engineering, drug delivery, and translational therapeutics, this article offers both a comprehensive overview and a realistic appraisal of the road ahead.

Open Access article:

Wang, D., Yin, F., Li, Z. et al. Current progress and remaining challenges of peptide–drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)?. J. Nanobiotechnol;23, 305 (2025). DOI: https://doi.org/10.1186/s12951-025-03277-2

Lin Wang, Ph.D.
Member, Scientific Advisory Board, Boulder Peptide Society
Director of Analytical Development, Gilead Sciences
https://www.linkedin.com/in/lin-wang-207b7836/