BACKGROUND: Targeting tumor metabolism reprogramming has demonstrated a synergistic antitumor effect in photodynamic therapy of triple-negative breast cancer (TNBC). However, such a combination therapeutic regimen has encountered challenges, such as limited photosensitizer bioavailability and severe drug toxicity. METHODS AND RESULTS: Herein, ultrasmall metal-organic frameworks (MOFs) nanodots (MSPC) that encapsulate metabolism inhibitors and mitochondria-targeted photosensitizers are designed and fabricated for synergistic photodynamic therapy (PDT) of TNBC. The MSPC exhibits an acidic-sensitive drug release, leading to glutathione depletion and mitochondrial respiration suppression. Significantly, MSPC substantially reduces intracellular adenosine triphosphate (ATP) levels by simultaneously disrupting oxidative phosphorylation and impeding aerobic glycolysis. Therefore, the glutathione depletion combined with metabolism inhibitor increases oxidative stress, which improves the efficacy of mitochondria-targeted PDT. Additionally, the increased retention of photosensitizers within tumors, facilitated by aggregation-enhanced retention (AER) effect, extends the time window for long-term fluorescence/photoacoustic imaging-guided PDT of TNBC. MSPC-sensitized PDT significantly suppresses tumor growth with a single-dose injection and repeatable PDT. CONCLUSIONS: In summary, these renal-clearable and aggregation-enhanced tumor-retained nanodots indicate the feasibility of overcoming resistance to reactive oxygen species induced by metabolic reprogramming, thus holding significant implications for boosting PDT of TNBC.