NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Biomimetic nanoprobe-augmented triple therapy with photothermal, sonodynamic and checkpoint blockade inhibits tumor growth and metastasis.

BACKGROUND: Comprehensive antitumor therapy through integrated multimodal means has drawn increasing attention owing to its high efficiency and metastasis suppression. RESULTS: We describe a synergistic triple protocol combining photothermal and sonodynamic therapy (PTT and SDT), together with immune checkpoint blockade for the inhibition of breast cancer growth and metastases in the 4T1 mouse model. PTT and SDT are synergistically augmented by a novel multimodal imaging nanoprobe integrated with cancer cell membrane-biomimetic nanoparticles (CHINPs) loaded with superparamagnetic iron oxide (SPIO) and hematoporphyrin monomethyl ether (HMME). CHINPs exhibit excellent homologous tumor targeting, and are sequentially triggered by ultrasound and near infrared (NIR) light under the guidance of magnetic resonance, photoacoustic and photothermal imaging, leading to complete in situ tumor eradication and systemic anti-tumor immune activation. Further combination of this approach with immune checkpoint blockade therapy is shown to suppress tumor metastasis. CONCLUSION: This work provides proof-of-principle for triple therapy using multimodal imaging-guided PTT/SDT based on biomimetic nanoprobes in combination with immunotherapy to eliminate tumors.

Tumor-self-targeted "thermoferroptosis-sensitization" magnetic nanodroplets for multimodal imaging-guided tumor-specific therapy.

Ferroptosis-based nanomedicine has drawn increasing attention in antitumor therapy because of the advantages of this unconventional mode of apoptosis, but the difficulties of delivery to the tumor site and surface-to-core penetration after arrival seriously hinder further clinical transformation and application. Herein, we propose an unprecedented strategy of injecting magnetic nanodroplets (MNDs) to solve these two longstanding problems. MNDs are nanocarriers that can carry multifunctional drugs and imaging materials. MNDs can effectively accumulate in the tumor site by active tumor targeting (multifunctional drugs) and passive tumor targeting (enhanced permeability and retention effect), allowing diffusion of the MNDs from the surface to the core through mild-temperature magnetic fluid hyperthermia (MHT) under multimodal imaging guidance. Finally, the ferroptosis pathway is activated deep within the tumor site through the drug release. This approach was inspired by the ability of mild-temperature MHT to allow MNDs to quickly pass through the blood vessel-tumor barrier and deeply penetrate the tumor tissue from the surface to the core to amplify the antitumor efficacy of ferroptosis. This strategy is termed as "thermoferroptosis sensitization". Importantly, this behavior can be performed under the guidance of multimodal imaging, making the design of MNDs for cancer therapy safer and more reasonable.