NIR II-Guided Photoactivatable Silencing Polyplex Boosts Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Nanotechnology

Background:

• Photodynamic therapy (PDT) enhances cancer immunotherapy by inducing immunogenic cell death (ICD).
• Limitations of first and second-generation photosensitizers include shallow tissue penetration, hindering anti-tumor efficacy.
• There is a need for advanced photosensitizers with improved penetration and therapeutic capabilities.

Purpose of the Study:

• To develop a novel near-infrared (NIR) absorbing polymer, PTSQ, for enhanced PDT and siRNA delivery.
• To create PTSQ/siPD-L1 complexes for combined PDT and immune checkpoint blockade therapy.
• To evaluate the efficacy of this combined approach in preclinical cancer models.

Main Methods:

• Synthesized a custom polymer (PTSQ) with NIR absorption and NIR II fluorescence.
• Formulated PTSQ into self-assembled nanomicelles for siRNA delivery.
• Developed PTSQ/siPD-L1 complexes for combined PDT and PD-L1 blockade.
• Assessed cellular ICD induction and PD-L1 gene suppression.
• Evaluated in vivo anti-tumor efficacy in CT26, 4T1, and patient-derived xenograft (PDX) models.

Main Results:

• PTSQ demonstrated efficient PDT and siRNA delivery in the NIR and NIR II regions.
• PTSQ/siPD-L1 complexes effectively induced ICD and suppressed PD-L1 expression.
• In vivo studies showed significant tumor growth inhibition in multiple cancer models.
• The treatment activated immune cells, including T cells, dendritic cells, and macrophages, reversing the tumor microenvironment.

Conclusions:

• NIR II-guided PDT combined with siPD-L1 therapy offers a promising strategy for cancer treatment.
• PTSQ nanomicelles serve as an effective platform for combined PDT and gene silencing.
• This approach enhances anti-tumor immunity through ICD induction and immune cell activation.