Photodynamic therapy (PDT) represents a promising strategy for tumor treatment. However, the development of PDT-based antitumor therapies faces challenges stemming from the hypoxic nature of the tumor microenvironment and the limited penetration of photosensitizers. This study presents a novel class of antitumor nanoparticles, designated as ARLN-FP, engineered to penetrate tumor tissues deeply and inhibit tumor growth through the generation of oxygen-independent free radicals. With the encapsulation of IR780 and dimethyl 2,2 '-azobis(2-methylpropionate) (AIBME) in the core of ARLN-FP, near-infrared (NIR) laser irradiation of ARLN-FP with induced heat generation, which subsequentially led to the decomposition of AIBME and the production of free radicals without relying on oxygen. In vitro studies indicated that ARLN-FP penetrated more than 100 mu m into multicellular tumor spheroids, demonstrating its enhanced tissue permeability. Animal studies confirmed the anti-tumor effects of ARLN-FP-mediated photonic thermodynamic therapy, where the oxygen-independent radical formation contributed to successful tumor eradication, evidenced by a significant tumor inhibition rate of 90.8% after 22 days. This research presents a feasible method to overcome the limitations of traditional oxygen-dependent photodynamic therapies, which offers a new approach to developing nanomedicines to overcome resistance in deep and hypoxic tumor regions.

ARLN-FP successfully delivered photothermal agents and radical initiators to deep tumor tissues, resulting in the production of oxygen-independent radicals that effectively inhibit tumor growth. Unlike conventional photodynamic therapies, the ARLN-FP can produce cytotoxic free radicals even in severely hypoxic conditions within deep tumor tissue when exposed to laser irradiation.