A triple‐stage precision nanogel platform in which carbon dots serve as organelle‑targeted delivery vehicles that achieved over 85% tumor growth inhibition with minimal systemic toxicity and offers a promising strategy to overcome key barriers in cancer therapy.
Abstract
Conventional chemotherapy is limited by poor cellular uptake and low tumor selectivity, often requiring high systemic doses that increase off‑target toxicity. Here we report a triple‑stage precision nanogel (CDX@nano) in which carbon dots (CDs) serve as organelle‑targeted delivery vehicles. The nanogel is surface‐functionalized with indomethacin for tumor‑specific homing and encapsulates CDs conjugated with doxorubicin (DOX) via glutathione‐cleavable disulfide linkages. Upon near‐infrared irradiation, the CDs generate singlet oxygen, triggering nanogel disassembly, and rapid drug release. The liberated CDs accumulate in mitochondria, elevating reactive oxygen species and disrupting redox homeostasis, while DOX translocates to the nucleus to induce DNA damage. This cascade‐activated, dual‐compartment assault integrates photodynamic and chemotherapeutic modalities. In vitro, CDX@nano reduced tumor cell viability to 8.5% upon irradiation, showing approximately 4.5‑fold greater potency than non‐targeted controls. In vivo, it achieved over 85% tumor growth inhibition with minimal systemic toxicity. This triple‐stage platform offers a promising strategy to overcome key barriers in cancer therapy.
Combination therapies hold significant promise for breast cancer treatment; however, conventional delivery systems often lack precise control over intracellular drug release, limiting delivery efficiency and therapeutic synergy. To address this, we engineered triple stimuli-responsive nanoparticles (HAP/PDA NPs) by coating prodrug HA-PPT (HAP; HA = hyaluronic acid, PPT = podophyllotoxin) with ester and disulfide bonds onto polydopamine (PDA) cores for synergistically combining chemotherapy, photothermal therapy, and immunotherapy. HAP/PDA NPs exhibited tumor microenvironment-responsive drug release triggered by low pH, high glutathione levels, and localized heat, achieving a cumulative PPT release of 90.9% under triple-stimuli conditions. Furthermore, the NPs enhanced photpthermal therapy efficacy by downregulating heat shock protein 70 expression, mitigating thermoresistance. Notably, the mechanism involved suppression of the immune checkpoint fibrinogen-like protein 1 (FGL-1) by HAP/PDA NPs via the JAK2/STAT3 axis, with FGL-1 expression reduced to approximately 40% of the control level, thereby reversing immunosuppression to activate antitumor immunity and drive primary tumor regression. As a result, this multimodal approach enabled complete inhibition of tumor growth in some subjects and maintained high efficacy with a markedly lower PPT dose (one-third of the conventional dose). These findings offer a mechanistic paradigm for designing precision nanomedicines that co-target molecular and immune pathways for improved combination therapy in refractory breast cancer.
Min Li, Jiao Sun, Jie An et al.· Colloids and Surfaces B: Bio...· 0 citations
Achieving precise drug delivery to the tumor site can minimize systemic side effects caused by off-target effects. As a therapy that depends on oxygen content, photodynamic therapy (PDT) is significantly constrained by the hypoxic nature of the tumor microenvironment (TME). Compared with the limited efficacy of single PDT, the combination of multiple treatment modalities can achieve synergistic enhancement and superior therapeutic outcomes. Since carbon radical therapy does not rely on oxygen as a reactive substrate, it is mechanistically complementary to oxygen-dependent PDT. In this work, we report a novel strategy for developing a theranostic nanoplatform for long-lasting PDT activated by 1530 nm laser irradiation and glutathione (GSH)-triggered carbon-centered radical synergistic therapy that responds specifically to the TME. This theranostic nanoplatform (UCNPs@WOR:AF@CDC, UWAC) comprises three components: GSH-responsive engineered vesicles (CDC), functionalized metal-organic frameworks (WOR) encapsulating lanthanide upconversion nanoparticles (UCNPs@WOR, UW), and carbon radical prodrugs (ART-Fe, AF). Lanthanide-based upconversion nanoparticles (UCNPs) could upconvert 1530 nm light to 1390 nm for attenuation-minimized second near-infrared (NIR-II) fluorescence imaging and to visible light that serves as the light source for photocatalysis for water oxidation. The 1530 nm light-activated generation of reactive oxygen species (ROS), enhanced by UW-mediated hydrolytic oxygen evolution, works in synergy with the GSH-triggered release of the carbon radical prodrug (AF) to achieve long-lasting therapeutic outcomes. Importantly, it could achieve tumor-specific drug release, triggered by the degradation of the engineered vesicles in response to elevated GSH levels. This work develops a novel theranostic nanoplatform, which could achieve GSH-activated drug delivery, deep-tissue penetration, and a long-lasting therapeutic effect.
Jitong Gong, Yu Liu, Qingkun Yang et al.· ACS Applied Materials and In...· 0 citations
ABSTRACT Precision control over nucleic acid delivery remains a critical challenge in cancer therapy, particularly for siRNA‐based gene silencing, where off‐target effects limit clinical translation. Herein, we report a programmably engineered DNA nanocircuit with cascaded dual‐AND logic gates, which enables the development of a spatiotemporally controlled siRNA delivery strategy for precision cancer therapy. The DNA nanocircuit is engineered to respond to three tumor‐specific signals in a sequential manner: extracellular acidic pH, membrane‐overexpressed nucleolin (NCL), and intracellular glutathione (GSH). The first AND gate is activated by the co‐occurrence of acidic pH and NCL, triggering a conformational rearrangement that generates a molecular output. This integrated output, combined with intracellular GSH, serves as the dual input to co‐activate the second AND gate, initiating siRNA release via a cascade reaction inherent to the DNA circuit. As a proof‐of‐concept, when harnessing this DNA circuit in a temozolomide (TMZ)‐resistant glioblastoma (GBM) mouse model, we demonstrate that this design ensures highly selective release of siPARP1 in GBM cells, achieving efficient PARP1 silencing, reversed TMZ resistance, and minimized off‐target toxicity. Collectively, the cascaded dual‐AND logic, enabled by precise DNA sequence programming, represents a generalizable strategy for multi‐signal‐responsive delivery systems, highlighting the potential of DNA circuits in precision cancer therapy.
Yan Zhao, Yufei Lan, Min‐Goo Lee et al.· Advancement of science· 0 citations
Low tumor immunogenicity and limited immune‐cell infiltration remain major barriers to effective breast cancer immunotherapy. Although sonodynamic therapy (SDT) offers a noninvasive strategy for deep‐tissue tumor treatment, its efficacy is often restricted by insufficient reactive oxygen species (ROS) generation and the immunosuppressive tumor microenvironment. Here, we report a sonosensitizer‐functionalized polymetallic nanozyme, Pd@PtBi2‐Ce6@HA (PPBCH), as a multifunctional theranostic platform for photoacoustic imaging‐guided sonodynamic cancer immunotherapy. Upon ultrasound (US) activation, PPBCH exhibits catalase‐, peroxidase‐, and glutathione oxidase‐like activities, thereby enabling O2 generation, ROS amplification, and intracellular glutathione depletion. This coordinated redox disruption induces mitochondrial dysfunction, lipid peroxidation, and GPX4 downregulation, leading to severe oxidative damage, ferroptotic stress, and subsequent immunogenic cell death. PPBCH also elicits canonical hallmarks of immunogenic cell death, including calreticulin exposure, HMGB1 release, and extracellular ATP secretion, thereby promoting dendritic cell maturation and antitumor immune activation. In parallel, the polymetallic framework enables photoacoustic imaging for monitoring tumor accumulation and guiding treatment timing in vivo. More importantly, PPBCH‐mediated SDT remodels the immunosuppressive tumor microenvironment, enhances CD8+ T‐cell infiltration, promotes M1‐like macrophage polarization, and markedly improves the therapeutic efficacy of anti‐PD‐L1 immunotherapy. This work establishes a polymetallic nanozyme strategy that integrates catalytic sonodynamic amplification, imaging‐guided intervention, and immunomodulation for precise cancer immunotherapy.
Caiying Li, Fangyi Pang, Yuzhen Ma et al.· SmartMat· 1 citation
The antioxidant defense barrier in the tumor microenvironment, particularly glutathione (GSH), considerably restricts the therapeutic efficacy of chemodynamic therapy (CDT). Moreover, CDT generally exhibits relatively mild therapeutic efficacy owing to its intrinsic reaction kinetics, making it difficult to achieve complete tumor eradication within a short time. To address these issues, we construct a functionalized nanotherapeutic platform, Nb2CTx@Ru-PEG2000-FA (NCRPF), for tumor photothermal ablation and enhanced CDT resulting from GSH depletion. NCRPF possesses three key advantages: 1. Efficient near-infrared II photothermal conversion (η = 42.08%), raising the tumor temperature above 45 °C within 90 s for rapid ablation; 2. Dual peroxidase-like and glutathione peroxidase-like activities, simultaneously depleting GSH and generating a burst of ·OH to eliminate residual tumors; 3. Targeted tumor accumulation with 2.9-fold higher efficiency than passive diffusion. Both in vitro and in vivo results confirm that this combined strategy achieves complete tumor eradication with favorable biosafety. Collectively, the NCRPF nanotherapeutic system provides a powerful new paradigm with high translational potential for the complete eradication of breast cancer.
We report the design and synthesis of a redox-responsive paclitaxel-BODIPY conjugate (PTX-SS-BDP) in which paclitaxel is linked to a BODIPY moiety through a glutathione-cleavable disulfide spacer. The amphiphilic conjugate readily self-assembles into PEGylated nanoparticles with excellent colloidal stability and efficient cellular uptake. Under intracellular reducing conditions, cleavage of the disulfide linker triggers the simultaneous release of paclitaxel and fluorescence ON response for the BODIPY reporter moiety, enabling real-time monitoring of prodrug activation. The nanoparticles exhibit glutathione-dependent drug release kinetics and preferential activation in MCF-7 breast cancer cells over normal MCF-10A mammary epithelial cells. Consequently, PTX-SS-BDP nanoparticles display enhanced cytotoxicity toward MCF-7 cells compared with free paclitaxel, while maintaining reduced toxicity toward MCF-10A cells. This study demonstrates a simple molecular strategy for constructing self-assembling fluorogenic prodrugs that integrate redox-responsive chemotherapy with fluorescence-guided monitoring.
D. Tayde, Raviranjan Pandey, Amitva Das et al.· Organic and biomolecular che...· 0 citations