Manipulating extracellular matrix to enhance intratumor drug delivery for nanomaterial-based photothermal therapy

Photothermal therapy (PTT), characterized by its minimally invasive nature and highly selective tumor-killing ability, holds great potential for tumor therapy. Due to the outstanding photothermal performance and tumor targeting ability, nanomaterial-based photothermal agents (nano-PTAs) have further expanded the therapeutic horizons of PTT. However, the dense and complicated network of the tumor extracellular matrix (ECM) severely restricts the penetration of nano-PTAs into deep tumor tissues. Since elevated temperatures are only generated in the vicinity of nano-PTAs upon laser irradiation, the uneven distribution of these agents leads to incomplete tumor coverage across the tumor. Consequently, overcoming ECM barriers and enhancing tumor permeability are critical for the success of tumor PTT. To address this challenge, researchers have explored strategies that combine tumor ECM regulation with PTT to facilitate the deep diffusion of nano-PTAs. This review summarizes the latest advancements in designing nano-PTAs with ECM-remodeling capabilities, aiming to enable their uniform penetration throughout tumors. Additionally, we discuss the remaining obstacles and challenges in elucidating the mechanisms of ECM manipulation and understanding the interactions between nano-PTAs and ECM components during the penetration process.