Biomolecule-Photosensitizer Conjugates: A Strategy to Enhance Selectivity and Therapeutic Efficacy in Photodynamic...

Biomolecule-photosensitizer conjugates have rapidly evolved into one of the most powerful strategies for improving the selectivity, efficacy, and translational potential of photodynamic therapy (PDT). By integrating photosensitizers (PSs) with carbohydrates, amino acids, peptides, aptamers, proteins, cofactors, vitamins or antibodies, these constructs overcome long-standing limitations of classical PDT, including poor solubility, insufficient tumour accumulation, and strong dependence on oxygen availability. Beyond enhancing receptor-mediated uptake and enabling precise interactions with the tumour microenvironment (TME), bioconjugation also modulates aggregation, photochemical properties, intracellular accumulation, and immune system activation. A particularly transformative trend is the emergence of supramolecular architectures in which photosensitizers form defined nanostructured aggregates with peptides or proteins. Once considered an undesirable phenomenon, aggregation is now recognized as a tenable feature that governs photochemical behaviour. Engineered aggregates can undergo environment-triggered disassembly to monomeric, photoactive states, or operate as semiconductor-like nanodomains capable of Type I reaction through symmetry-breaking charge separation. This shift toward oxygen-independent radical pathways offers a promising solution to the challenge of hypoxia, a hallmark of the TME that severely compromises conventional Type II PDT. Parallel advances in 3D experimental platforms such as tumour organoids and organ-on-chip systems provide physiologically relevant validation of these conjugates, enabling the assessment of penetration, subcellular localization, immunogenic cell death, and therapeutic synergy within realistic TME conditions. Collectively, the integration of biomolecular targeting with controlled supramolecular design is redefining the landscape of PDT. Future progress will depend on designing conjugates that retain high activity under hypoxia, engineering dynamic aggregate states, and systematically validating these systems in advanced TME-mimetic models. Together, these developments position biomolecule-photosensitizer conjugates as a versatile and increasingly less oxygen-dependent class of next-generation phototherapeutic agents.