A Photosensitizer Discretely Loaded Nanoaggregate with Robust Photodynamic Effect for Local Treatment Triggers Systemic Antitumor Responses

Photodynamic therapy (PDT), is a rising star for suppression of in situ and metastatic tumors, yet it is impeded by low ROS production and off-target phototoxicity. Herein, an aggregation degree editing strategy, inspired by gene editing, was accomplished by the coordination of an aggregation degree editor, p(MEO₂MA₁₆₀-co-OEGMA₄₀)-b-pSS₃₀ [POEGS; MEO₂MA = 2-(2-methoxyethoxy)ethyl methacrylate, OEGMA = oligo(ethylene glycol) methacrylate; pSS = poly(styrene sulfonate)] and indocyanine green (ICG) to nontoxic Mg²⁺, forming an ICG discretely loaded nanoaggregate (ICG-DNA). Optimization of the ICG aggregation degree [POEGS/ICG (P/I) = 6.55] was achieved by tuning the P/I ratio, alleviating aggregation-caused-quenching (ACQ) and photobleaching concurrently. The process boosts the PDT efficacy, spurring robust immunogenic cell death (ICD) and systemic antitumor immunity against primary and metastatic immunogenic “cold” 4T1 tumors via intratumoral administration. Moreover, the temperature-sensitive phase-transition property facilitates intratumoral long-term retention of ICG-DNA, reducing undesired phototoxicity to normal tissues; meanwhile, the photothermal-induced tumor oxygenation further leads to an augmented PDT outcome. Thus, this simple strategy improves PDT efficacy, boosting the singlet oxygen quantum yield (Φ_Δ)-dependent ICD effect and systemic antitumor responses via local treatment.