Carrier-free supramolecular co-assembly enables oxygen-economizing photodynamic therapy via mitochondrial respiration suppression

Hypoxia within the tumor microenvironment severely compromises the therapeutic efficacy of photodynamic therapy (PDT) by limiting oxygen-dependent reactive oxygen species (ROS) generation. Although extensive efforts have been devoted to oxygen-supplementation strategies, most existing approaches provide only transient hypoxia relief and are hindered by limited oxygen-loading capacity, premature oxygen leakage, and insufficient catalytic efficiency. Herein, we report a carrier-free self-assembly nanodrug (BBR-Ce6 NPs) that enhances PDT through a durable oxygen-economizing strategy by reducing mitochondrial oxygen consumption rather than directly supplying oxygen. The nanodrug is composed of the mitochondria-targeting oxidative phosphorylation (OXPHOS) inhibitor berberine (BBR) and the clinically used photosensitizer chlorin e6 (Ce6), which spontaneously co-assemble via synergistic π-π stacking and hydrogen-bonding interactions to form stable nanoparticles with high drug-loading efficiency. Benefiting from reversible noncovalent interactions, BBR-Ce6 NPs gradually disassemble within the mildly acidic tumor microenvironment, enabling tumor-responsive drug release. Following cellular internalization, BBR preferentially accumulates in mitochondria and inhibits mitochondrial complex I activity, thereby suppressing OXPHOS, reducing cellular oxygen consumption, and durably alleviating tumor hypoxia. This oxygen-sparing effect markedly enhances Ce6-mediated ROS generation and significantly improves PDT efficacy both in vitro and in vivo. In addition, the carrier-free formulation minimizes excipient-associated toxicity while simplifying nanoparticle fabrication. Collectively, this study establishes a safe and sustained hypoxia-relief strategy for enhancing PDT efficacy and offers a versatile nanoplatform for combining natural mitochondrial modulators with photosensitizers to overcome hypoxia-associated resistance of PDT in cancer treatment.