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

Abstract

Photodynamic therapy (PDT), is a rising star for suppression of <i>in situ</i> 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, <i>p</i>(MEO₂MA₁₆₀-<i>co</i>-OEGMA₄₀)-<i>b</i>-<i>p</i>SS₃₀ [POEGS; MEO₂MA = 2-(2-methoxyethoxy)ethyl methacrylate, OEGMA = oligo(ethylene glycol) methacrylate; <i>p</i>SS = 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 <i>via</i> 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 (<i>Φ</i>_Δ)-dependent ICD effect and systemic antitumor responses <i>via</i> local treatment.