Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.

Biodegradable Bismuth Nanostructures as a Ferroptosis Inducer for Phototherapy of Breast Cancer

“…Tumor tissues often exhibit high heterogeneity, characterized by an elevated ROS and glutathione (GSH) content in tumor cells. GSH, a primary cellular reducing agent, counteracts the therapeutic effects of PDT by clearing excessive ROS. − Ferroptosis, a form of cell death relying on ROS-induced lipid peroxidation (LPO), has emerged as a promising strategy in tumor therapy. Unlike other forms of cell death, ferroptosis involves oxidative damage to polyunsaturated fatty acids, disrupting cell structure and integrity. − Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis and a downstream product of GSH, plays a crucial role in mitigating LPO toxicity by catalyzing the reduction of hydrogen peroxide (H 2 O 2 ) and LPO to nontoxic lipid alcohol (LOH).…”

TME-Triggered Degradable Phototheranostic Nanoplatform for NIR-II Fluorescence Bioimaging-Guided Phototherapies and Immune Activation

“…PDT, akin to PTT, employs photosensitizers to generate cytotoxic reactive oxygen species (ROS) upon light exposure, damaging tumor cells by disrupting cell membranes and intracellular biomacromolecules. − In addition, it has been reported that ROS can inhibit the activity of HSP, amplifying the effectiveness of PTT. − Compared to complex nanoplatforms loaded with both photothermal agents and photosensitizers, phototheranostic agents capable of generating both ROS and local heating offer simplicity and safety advantages in synergizing PTT and PDT. , Moreover, synergistic PTT and PDT induce stronger immunogenic cell death (ICD) response, which is characterized by the release of damage-associated molecular patterns (DAMPs) such as calreticulin (CRT) exposure, extracellular release of adenosine triphosphate (ATP), and high mobility group box B1 (HMGB1), and release tumor-associated antigens, activating the immune system and facilitating tumor eradication. − …”