Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination.
Jianqin WanLulu RenXiaoyan LiShasha HeYang FuPeirong XuFanchao MengShiyun XianKanyi PuHangxiang WangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.
Keyphrases
- toll like receptor
- cell death
- reactive oxygen species
- inflammatory response
- small molecule
- photodynamic therapy
- papillary thyroid
- immune response
- nuclear factor
- squamous cell carcinoma
- small cell lung cancer
- squamous cell
- dna damage
- ejection fraction
- type diabetes
- fluorescence imaging
- bone marrow
- stem cells
- cancer therapy
- drug delivery
- oxidative stress
- mesenchymal stem cells
- skeletal muscle
- fluorescent probe
- drug release
- metabolic syndrome
- signaling pathway
- cell proliferation
- high dose
- combination therapy
- free survival
- anti inflammatory
- single cell
- patient reported
- drug induced
- replacement therapy