Metformin‐Mediated Immunosuppressive Microenvironment Remodeling in Combination with Chemotherapy via a Spatial‐Specific Multi‐Responsive Carrier‐Free Self‐Assembled Nanoparticle

Rapid advances in nanotechnology have made it possible to combine photothermal therapy (PTT) with immunotherapy, enabling to activate an in situ vaccine effect. However, this effect is severely impeded by low antigen presentation level and highly suppressive tumor immune microenvironment (immune “cold” tumors). To overcome the obstacles, multifunctional carrier‐free nanoparticles (FCDP‐NPs) assembled from Fe2+, toll‐like receptor 9 agonist (CpG), cationic lipid (DOTAP) and photothermal agent polydopamine are developed. After intratumoral injection, FCDP‐NPs carrying positive charge are exposed under laser irradiation, which can capture tumor‐associated antigens (TAAs) generated upon post‐PTT to form the nanovaccines (FCD‐NPs@TAAs). The nanovaccines further promote cross‐presentation of TAAs, stimulate adaptive immune responses, and shape immune “hot” tumors. As a result, in situ nanovaccines highly improve survival rates and elicit a durable immune memory that remarkedly prevents tumor metastasis, illustrating a useful platform for PTT synergized with immunotherapy.

Cascade Carrier‐Free Nanoparticles Forming In Situ Nanovaccines for Synergistic Photothermal‐Immunotherapy of Cancer

Huang,

Wang,

Yang

et al. 2024

Reinforcing Carrier‐Free Photothermal Nanodrugs Through Flavonol‐Driven Assembly

Fan,

Zheng,

Cheng

et al. 2024

Carrier‐free nanodrugs that integrate chemodrugs and other therapeutic agents demonstrate good efficacy and minimized side effects, showing promise for combined therapy. However, a key challenge lies in enhancing the bioavailability and therapeutic potential of the nanodrugs through a controllable assembly process. Herein, a carrier‐free photothermal nanodrug (ZPQ NPs) is constructed through flavonol‐driven assembly with amine‐substituted perylene diimide for enhanced chemo‐photothermal combined cancer therapy. The flavonol, particularly quercetin, facilitates J‐aggregation of perylene diimide derivatives within the nanodrug and contributes to multiple improvements, including red‐shifted absorption, enhanced fluorescence intensity, improved photothermal conversion efficiency as well as excellent photostability. Moreover, the nanodrug also demonstrates enhanced cellular uptake and intracellular reactive oxygen species scavenging capability. The combination of quercetin and photothermal effect effectively kills cancer cells, as well as alleviates inflammation following photothermal therapy. Guided by in vivo fluorescence imaging, the application of ZPQ NPs results in complete tumor elimination and effectively inhibits tumor recurrence through chemo‐photothermal combined therapy. This work presents a straightforward strategy for constructing carrier‐free nanodrugs that exhibit simultaneous enhancements in both photophysical properties and biological activity.

Dual‐Responsive Shape‐Transformable Charge‐Reversible Nanoparticles Combined with Chemo‐Photodynamic‐Immunotherapy for the Treatment of Breast Cancer and Lung Metastasis

Jia,

Gong,

Chen

et al. 2024

Herein, a dual‐responsive shape‐transforming charge‐reversal integrated nanomedicine system (DHP@BPP) is developed for the co‐delivery of the photosensitizer pyro pheophorbide‐α (Ppa), anti‐programmed cell death ligand 1 (PD‐L1) peptide (dPPA), and tumor‐associated macrophages (TAMs)‐regulating drug berberrubine (BBR). Hydrophobic Ppa and hydrophilic BBR are linked by matrix metalloproteinase‐2 (MMP‐2) responsive peptide (PMGMRKLVFF) to form BPP. BPP can self‐assemble into spherical nanoparticles with positive charge, which undergo shape transformation to nanofibers upon cleavage by MMP‐2 at tumor sites. The dPPA is conjugated with hexa‐histidine and polyethylene glycol to form DHP, which is then electrostatically adsorbed onto the surface of BPP to form DHP@BPP with negative surface charge. The DHP not only enhances the tumor‐targeting but also induces DHP disassociation and charge reversal of DHP@BPP due to protonation of histidine at the tumor site, thereby increasing tumor penetration while maintaining long blood circulation. Most importantly, through the combination of chemo‐photodynamic‐immunotherapy, it can repolarize TAMs from M2‐type to M1‐type while reducing PD‐L1 expression to reshape the immunosuppressive tumor microenvironment, thereby synergistically enhancing the effect of immunogenic cell death. In conclusion, this study offered a simple but effective idea for the treatment of immunosuppressive cancers through the combination of shape transformation and charge reversal, integrating chemo‐photodynamic‐immunotherapy.