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In situ therapy has shown great promise in treating unresectable tumors lacking tumor-supplying blood vessels. However, achieving precise delivery and sustained release of antitumor drugs, coupled with synergistic antitumor efficacy, remains a significant challenge. Here, by integrating β-CD-g-PEGMA (βCP) molecular brush hydrogel with functional carbon nanoflakes (CFe) and cisplatin, a novel in situ injectable hydrogel (denoted as CFe/βCP+Cis hydrogel) was designed. The reversible gel network of the βCP hydrogel and the rigid nanoscale structure of CFe endow the CFe/βCP+Cis hydrogel with properties conducive to injectability and long-term retention (over 63 days). The mixed CFe and cisplatin in the hydrogel are gradually released into tumor tissues, promoting synergistic antitumor efficacy through ferroptosis and cytotoxicity. Additionally, the CFe/βCP hydrogel can reduce the M2-like/M1-like ratio of macrophages, facilitate the infiltration of CD8+ T cells into the tumor microenvironment, and enhance antitumor immunity. Therefore, the CFe/βCP+Cis hydrogel demonstrates great potential for precise and sustained tumor treatment through chemokinetic therapy, chemotherapy, immunomodulation, and long-term retention characteristics.

Innovation Points: 1. Collaborative Innovation in Material and Structural Design: The core innovation of this study lies in the creative integration of β-CD-g-PEGMA molecular brush hydrogel with reversible physical cross-linking network and rigid carbonyl ferrocene (CFe) exhibiting enzyme-like catalytic activity. This ingenious combination of "soft" (flexible gel network) and "hard" (rigid nanoparticles) not only endows the composite hydrogel with excellent shear-thinning injection properties, but also achieves stable loading of CFe and the chemotherapeutic drug cisplatin through physical interactions, thus solving the problem of traditional formulations struggling to precisely reside and release over a long period of time in tumors without abundant blood vessels. 2. Multi-mechanism Collaborative Anti-tumor Strategy: This study goes beyond the simple function of a drug carrier, constructing a multifunctional platform integrating "drug delivery system" and "therapy execution unit". The gradual release of CFe (inducing ferroptosis through catalyzing the production of reactive oxygen species) and cisplatin (triggering DNA-damaging cytotoxicity) from the hydrogel at the tumor site do not act independently, but produce synergistic anti-tumor effects. This strategy, which integrates chemokinetic therapy and classical chemotherapy spatially and temporally within the same local delivery system, significantly enhances the killing efficiency against complex tumors. 3. Active Regulation of Tumor Immune Microenvironment: In addition to direct cell killing, this hydrogel system exhibits excellent immune regulatory functions. Studies have found that CFe/βCP hydrogel can remodel the immune cell population at the tumor site, reducing the proportion of immunosuppressive M2 macrophages and simultaneously promoting the infiltration of CD8+ T cells with tumor-killing capabilities. This characteristic of combining local treatment with systemic anti-tumor immune activation provides new possibilities for achieving distant inhibition of tumor recurrence and metastasis.

Scientific Research Inspiration 1. Inspiring the R&D Approach of "System Integration": This work profoundly reveals that the design of modern biomaterials should not be limited to the optimization of a single function, but should aim to construct an intelligent "microfactory" capable of orderly integrating multiple therapeutic modules (such as diagnosis, treatment, and immune regulation). Scientific research should start from how to achieve physical compatibility and functional synergy among different modules, and proceed with integrated design. 2. Emphasizing the Unique Value of "Local Long-Acting" in Solid Tumor Treatment: The study highlights the special significance of dosage forms that form in situ and remain for a long time for solid tumors lacking vascular supply. This inspires researchers to develop delivery technologies that can overcome physiological barriers and establish a lasting "drug depot" at the lesion site for these clinically refractory tumors. The strategic value of this approach may be higher than simply increasing the systemic drug dose. 3. Focusing on Exploring the Biological Effects of Materials Themselves: Carbon nanofluids (CFe) not only serve as drug carriers and ferroptosis inducers, but also participate in the reprogramming of the immune microenvironment. This suggests that in nanomedicine research, we should move beyond the traditional concept of viewing materials as inert "trucks" and delve into the biological effects brought by their inherent properties such as chemical composition, surface properties, and degradation products. These inherent properties may have unexpected synergistic or antagonistic effects with the loaded drugs.

Thought extension 1. Extending towards intelligentization of "on-demand response" and "temporal control": The current drug release system primarily relies on diffusion and gel degradation. In the future, it can further introduce chemical bonds or groups sensitive to the tumor microenvironment, enabling the release of CFe and cisplatin to respond to specific signals within the tumor, and even achieving temporal regulation of their release kinetics, for more precise and personalized treatment. 2. Deepening immune regulation mechanisms and exploring combined immunotherapy: Studies have observed the regulation of hydrogels on macrophages and T cells. Subsequent research can delve into its molecular mechanisms, such as clarifying through which signaling pathways CFe or gel degradation products exert their effects. Based on its immune activation characteristics, this hydrogel platform can be further combined with immune checkpoint inhibitors, locally reshaping the immune microenvironment to enhance systemic immunotherapy, potentially forming a powerful "in situ vaccine" effect. 3. Expanding indications and multifunctional integration: This research idea can be extended to the treatment of other solid tumors rich in stroma or postoperative residual cavities. At the same time, near-infrared dyes, acoustic sensitizers, or radioactive isotopes can be integrated into this gel system, endowing it with imaging (such as photoacoustic and magnetic resonance imaging) guidance capabilities, or combining with multimodal treatments such as photothermal/sonodynamic/radiotherapy, to construct an integrated "diagnosis-treatment-monitoring" platform to address the high heterogeneity and evolution of tumors.
Similar research ideas: 1. In-situ gel system based on other functional nanomaterials: Drawing inspiration from the introduction of carbon nanozymes in this study, other nanomaterials with unique functions (such as black phosphorus quantum dots with photothermal effect, cerium oxide nanozymes capable of catalyzing the decomposition of endogenous tumor substances, or metal-organic frameworks that can regulate cell metabolism) can be combined with temperature-sensitive, pH-responsive, or enzyme-crosslinked hydrogels. The goal is also to construct a local treatment platform that combines good injectability, long-term retention capacity, and self-treatment function. 2. Multi-drug gel library for combined immunotherapy: Inspired by the synergistic treatment and immune regulation in this study, in-situ gels capable of co-loading multiple immune modulators and chemotherapeutic/targeted drugs can be designed. This "local cocktail therapy" aims to create a high-concentration zone within the tumor where multiple immune stimulators coexist, more effectively reversing the immunosuppressive microenvironment and systematically activating anti-tumor immune responses, especially for "cold tumors" that are insensitive to monotherapy immunotherapy. 3. Construction of tissue-engineered therapeutic scaffolds: Applying the idea of injectable, functionalized hydrogels to the field of tumor surgery, "tissue-engineered" anti-recurrence scaffolds for postoperative residual cavity filling can be developed. The gel can not only physically fill the cavity and control bleeding, but also its loaded sustained-release drugs can continuously act on potentially residual small lesions in the surrounding area, inhibiting local recurrence and excessive formation of fibrous scars. Meanwhile, its three-dimensional porous structure can also serve as a matrix for recruiting and cultivating beneficial immune cells, promoting healthy tissue repair.

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