The rational design of tumor microenvironment (TME)‐activated nanomedicine is driving a new direction in tumor immunology. Furthermore, the novel therapeutic mode of ultrasound‐triggered sonodynamic therapy (SDT) has been proven to specifically activate the immune response. Herein, a well‐defined covalent organic framework (COF) with sonosensitive properties is synthesized through experimental and theoretical verification, followed by the efficient loading of the toll‐like receptor agonist (Poly(I:C)) and in situ growth of paramagnetic transitional metallic oxide of manganese bioxide (MnO2). The MnO2‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn2+, simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H2O2) and produce oxygen, facilitating SDT‐induced reactive oxygen species production, and inducing immunogenic cell death, thereby boosting immune engine and triggering abundant neoantigen exposure. With the powerful assistance of immunological agents Mn2+ and Poly(I:C), the triggered immune engine is amplified by refueling the engine (stepping on the accelerator) to reduce the immunosuppressive state. Overall, this study improves the synthesis of multifunctional COF and expands its application. The developed nano‐sonosensitizer system provides a paradigm to enhance SDT‐based high‐performance multifunctional sonosensitizers, and this SDT‐mediated strong tumor‐suppressive efficiency and activated immune effect represent a promising combinatorial therapeutic strategy for cancer therapy.

A lack of targeting accuracy and radiosensitivity severely limits clinical radiotherapy. In this study, we developed a radiosensitizer comprised of Ru-based metal-organic nanostructures (ZrRuMn-MONs@mem) to optimize irradiation by maximizing reactive oxygen species (ROS) generation and CO release in X-rayinduced dynamic therapy (XDT). The well-designed nanostructures increase the direct absorption of radiation doses (primary radiation) and promote the deposition of photons and electrons (secondary radiation). The secondary electrons were trapped and transferred in the constrained MONs where they induce a cascade of reactions to increase the therapeutic efficiency. Meanwhile, the full-length antiglypican 3 (GPC3) antibody (hGC33) expressed a cell membrane coating enabling active targeting of tumor sites with optimized biocompatibility. The ZrRuMn-MONs@mem represents a starting point for advancing an all-around radiosensitizer that operates efficiently in clinical XDT.

In view of the great challenges related to the complexity and heterogeneity of tumors, efficient combination therapy is an ideal strategy for eliminating primary tumors and inhibiting distant tumors. A novel aggregation‐induced emission (AIE) phototherapeutic agent called T‐TBBTD is developed, which features a donor–acceptor–donor (D–A–D) structure, enhanced twisted molecule conformation, and prolonged second near‐infrared window (NIR‐II) emission. The multimodal imaging function of the molecule has significance for its treatment time window and excellent photothermal/photodynamic performance for multimode therapy. The precise molecular structure and versatility provide prospects for molecular therapy for anti‐tumor applications. Fluorescence imaging in the NIR‐II window offers advantages with enhanced spatial resolution, temporal resolution, and penetration depth. The prepared AIE@R837 NPs also have controllable performance for antitumor photo‐immunotherapy. Following local photo‐irradiation, AIE@R837 NPs generate abundant heat, and 1O2 directly kills tumor cells, induces immunogenic cell death (ICD) as a photo‐therapeutic effect, and releases R837, which enhances the synergistic effect of antigen presentation and contributes to the long‐lasting protective antitumor immunity. A bilateral 4T1 tumor model revealed that this photo‐immunotherapy can eliminate primary tumors. More importantly, it has a significant inhibitory effect on distant tumor growth. Therefore, this method can provide a new strategy for tumor therapy.

Photodynamic therapy (PDT) is an alternative cancer treatment technique with a noninvasive nature, high selectivity, and minimal adverse effects. The indispensable light source used in PDT is a critical factor in determining the energy conversion of photosensitizers (PSs). Traditional light sources are primarily concentrated in the visible light region, severely limiting their penetration depth and making them prone to scattering and absorption when applied to biological tissues. For that reason, its efficacy in treating deep‐seated lesions is often inadequate. Self‐exciting PDT, also known as auto‐PDT (APDT), is an attractive option for circumventing the limited penetration depth of traditional PDT and has acquired significant attention. APDT employs depth‐independent internal light sources to excite PSs through resonance or radiative energy transfer. APDT has considerable potential for treating deep‐tissue malignancies. To facilitate many researchers' comprehension of the latest research progress in this field and inspire the emergence of more novel research results. This review introduces internal light generation mechanisms and characteristics and provides an overview of current research progress based on the recently reported APDT nanoplatforms. The current challenges and possible solutions of APDT nanoplatforms are also presented and provide insights for future research in the final section of this article.

It is an engaging program for tumor treatment that rationalizes the specific microenvironments, activation of suppressed immune system (immune resistance/escape reversion), and synergistic target therapy. Herein, a biomimetic nanoplatform that combines oxidative stress with genetic immunotherapy to strengthen the therapeutic efficacy is developed. Ru‐TePt nanorods, small interfering RNA (PD‐L1 siRNA), and biomimetic cellular membrane vesicles with the targeting ability to design a multifunctional Ru‐TePt@siRNA‐MVs system are rationally integrated. Notably, the Fenton‐like activity significantly enhances Ru‐TePt nanorods sonosensitization, thus provoking stronger oxidative stress to kill cells directly. Meanwhile, immunogenic cell death is triggered to secrete numerous cytokines and activate T cells. The effective catalase characteristics of Ru‐TePt enable the in situ oxygen‐producing pump to improve tumor oxygen level and coordinately strengthen the therapeutic effect of SDT followed. More importantly, anti‐PD‐L1‐siRNA mediated immune checkpoint silence of the PD‐L1 gene creates an environment conducive to activating cytotoxic T lymphocytes, synergistic with boosted reactive oxygen species‐triggered antitumor immune response. The experimental results in vitro and in vivo reveal that the Ru‐TePt@siRNA‐MVs nanosystems can effectively activate the oxidative stress‐triggered immune response and inhibit PD‐1/PD‐L1 axis‐mediated immune resistance. Consequently, this orchestrated treatment paradigm provides valuable insights for developing potential oxidative stress and genetic immunotherapy.