NO-PDT and chemotherapy: spatiotemporal control to achieve therapeutic synergy.

Combination cancer therapies exploit additive and synergistic effects by simultaneously engaging multiple active species or mechanisms, either along a single pathway or across parallel ones to maximize therapeutic efficacy while minimizing side effects. Among emerging strategies, nitric oxide (NO)-based photodynamic therapy (NO-PDT) has attracted growing interest as a powerful alternative to conventional PDT, owing to the multifaceted roles of NO in tumor biology. Over the past several years, our group has pursued the rational design of molecular and supramolecular systems that integrate NO-PDT with conventional chemotherapeutic agents, exploiting both covalent and non-covalent approaches to co-localize all active components within the same spatial region without compromising their individual properties. This account describes the conceptual evolution and key advances from our laboratories in this area, highlighting the design principles underlying each platform and the mechanistic rationale connecting structure to function. We also provide a brief overview of NO's specific roles in the tumor microenvironment, which underpin the biological logic of our approach. Taken together, our results demonstrate that NO-PDT-based combination systems represent a versatile and effective strategy in cancer research, with promising potential for further development.