Breaking the Hypoxia Barrier: Supramolecular Nanoassemblies Empower Photodynamic Therapy of Tumors

Supramolecular chemistry provides an efficient and transformative strategy for the modular integration of diverse active pharmaceutical ingredients (APIs) into nanoassemblies through weak, reversible noncovalent interactions, combining the native features of the original molecules with additional functionalities derived from supramolecular structures. Thanks to ultra-high photosensitizer or API loading, on-demand delivery, facile multifunction integration, scalability, and potentially simplified regulatory pathways, supramolecular nanoassemblies markedly enhance the clinical translatability of nanomedicine. In particular, rational design of these systems can overcome hypoxia barriers, revitalizing photodynamic therapy (PDT) against tumors. Despite clinical approval of PDT for cancer therapy over four decades ago, it has yet to achieve widespread adoption as a first-line modality, largely due to the technological bottleneck of tumor hypoxia. In this review, we systematically summarize recent advances in supramolecular nanoassemblies for hypoxic tumor PDT, categorizing them into four key design principles: enriching intratumoral oxygen levels, minimizing oxygen dependence, leveraging tumor hypoxia, and enabling PDT-involved synergistic therapies. We also discuss the intrinsic properties, advantages, and building motifs of supramolecular nanoassemblies. Finally, we highlight current challenges and future perspectives, aiming to broaden the research landscape and accelerate clinical and commercial translation.