低氧微环境和光敏剂在固体肿瘤中的有限渗透是限制光动力治疗（PDT）疗效的两个关键因素。在本研究中，我们开发了一种新型氟化混合胶束（M60@PFC-Ce6）作为一种穿透肿瘤和富氧的纳米平台，由氯明绿（Ce6）和全氟碳化合物（PFCs）共同负载到氟化胶束中，以缓解低氧条件，并具有促进靶向分布于肿瘤实体的叶酸作为靶向配体。将氟化共聚物纳入混合胶束中，不仅大大增加了氧载荷能力，还改善了液体PFCs乳化物在胶束内的稳定性，避免泄漏。M60@PFC-Ce6表现出优异的输送氧气能力，良好的细胞内活性氧（ROS）生成能力，以及对2D单层细胞和3D多细胞球模型的出色光毒性。这些结果表明，叶酸靶向能力带来的富氧输送和细胞摄取增加，增强了ROS产生和PDT疗效。M60@PFC-Ce6进入3D细胞球的穿透研究证实，小胶束尺寸和叶酸共轭对胶束穿透和积累有益。因此，我们提供了一种具有丰富的氧载荷量、更好的药物穿透和稳定的胶束特性，能够缓解肿瘤低氧和提高PDT疗效的新型纳米平台。本文受版权保护。版权所有。

Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict the efficacy of photodynamic therapy (PDT). Herein, we developed a new fluorinated mixed micelle (M60@PFC-Ce6) as a tumor-penetrating and oxygen-enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co-loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitate the selective biodistribution within tumor solids. Incorporation of fluorinated copolymers into mixed micelles exhibits not only to greatly increase the oxygen-loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC-Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulted from folate-targeted ability enhance ROS production and PDT efficacy. The penetration study of M60@PFC-Ce6 into a 3D spheroid confirms the small micellar size and folate conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, we provide a new nanoplatform with enriched oxygen-carrying amount, better drug penetration and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.