Triple-action cancer therapy using laser-activated NO-releasing metallomicellar nanophotosensitizer for pyroptosis-driven immune reprogramming

Ayeskanta Mohanty; Adityanarayan Mohapatra; Aravindkumar Sundaram; Padmanaban Sathiyamoorthy; Woongkyu Park; Santhosh Kalash Rajendrakumar; In-Kyu Park

doi:10.1016/j.jconrel.2025.01.012

Triple-action cancer therapy using laser-activated NO-releasing metallomicellar nanophotosensitizer for pyroptosis-driven immune reprogramming

J Control Release. 2025 Jan 9:379:147-163. doi: 10.1016/j.jconrel.2025.01.012. Online ahead of print.

Authors

Ayeskanta Mohanty¹, Adityanarayan Mohapatra², Aravindkumar Sundaram², Padmanaban Sathiyamoorthy¹, Woongkyu Park³, Santhosh Kalash Rajendrakumar⁴, In-Kyu Park⁵

Affiliations

¹ Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
² Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju 61469, Republic of Korea; DR.Cure Inc., Hwasun 58128, Republic of Korea.
³ Photonic Energy Components Research Center, Korea Photonics Technology Institute (KOPTI), Gwangju 61007, South Korea.
⁴ Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom.
⁵ Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju 61469, Republic of Korea; DR.Cure Inc., Hwasun 58128, Republic of Korea. Electronic address: pik96@jnu.ac.kr.

PMID: 39788373
DOI: 10.1016/j.jconrel.2025.01.012

Abstract

Cancer photoimmunotherapy represents an intelligent and highly efficient therapeutic approach that harnesses the photothermal effect to precisely target and ablate tumor tissues, while simultaneously modulating the immune system to achieve tumor elimination. The integration of multifunctional therapeutic modalities for combined photoimmunotherapy requires advanced drug delivery systems. However, the design of a single nanoagent capable of serving as a multifunctional nanophotosensitizer remains a significant challenge. In this study, we developed a metallomicellar nanophotosensitizer named TAGNO, which offers a synergistic tri-modal cancer treatment strategy by combining photothermal therapy (PTT), gas therapy (GT), and immunotherapy. The TAGNO nanophotosensitizer consists of a gold nanorod core, responsible for inducing the photothermal effect, coated with an amphiphilic polymer functionalized with tumor cell penetrating peptide to accommodate lipophilic small molecule BNN6, a nitric oxide (NO) donor for GT. We demonstrated that TAGNO exhibited high tumor accumulation, excellent stability, and biocompatibility, ensuring the safe delivery of NO to the tumor site. Upon near-infrared (NIR) laser irradiation, TAGNO effectively raised the temperature within tumor tissues while sparing the surrounding healthy tissues and enabled controlled NO release. Once released, the NO interacts with hydrogen peroxide in the hypoxic tumor microenvironment, forming peroxynitrite (ONOO^-), which induces mitochondrial dysfunction and triggers pyroptotic cell death. Pyroptosis induced immunogenic cell death and the subsequent release of tumor antigens, activating cytotoxic T cells and promoting M1 macrophage polarization, effectively controlling both primary and secondary tumor growth. Furthermore, laser-induced NO release facilitated the relaxation of stiff tumor tissues, enhancing blood vessel dilation and oxygenation. This improvement promoted immune cell infiltration while suppressing immunosuppressive cells. Overall, this innovative combination of PTT, GT, and immunotherapy presents a potent and synergistic strategy for the treatment of malignant colon tumors, achieving complete tumor eradication.

Keywords: Cancer immunotherapy; Colon cancer; Gas therapy; Nanophotosensitizer; On-demand NO release; Phototherapy.