基础理论：磁性纳米颗粒(MNPs)是临床中使用最广泛的无机纳米颗粒，具有治疗和成像功能，但其磁热转化效率低、泄漏快、分布不均会降低其在肿瘤成像和治疗方面的敏感性和治疗效果。 方法：我们合理设计了一个系统，包含pH可控的电荷可逆的MNPs(M20@DPA/HA)和不同尺寸的负电荷MMPs(M5和M20)，可以引起细胞内聚集。 MNPs表面的肼基和透明质酸（HA）的醛基形成了具有pH可控性的动态腐蚀酸酐键。在酸性pH下，研究了由M20@DPA/HA和M5 (M5&20)或M20@DPA/HA和M20 (M20&20)组成的复合物的细胞内聚集。此外，通过一系列细胞和动物模型实验，探究了肿瘤细胞的磁致热治疗(MHT)效率、肿瘤相关巨噬细胞极化、巨细胞形成和肿瘤微环境免疫激活等方面。 结果：通过物理化学表征，聚集系统(M20&20)与单个MNPs相比，磁热转化效率显著提高20倍，同时在肿瘤组织内具有增强的渗透和保留能力。此外，它可促进免疫激活，包括肿瘤相关巨噬细胞极化，以及形成巨细胞以招募T细胞。因此，M20&20聚集系统在4T1小鼠乳腺肿瘤模型中实现高度抑制，经磁致热治疗后，几乎没有肿瘤生长和转移。 结论：我们开发了一个受控的细胞内聚集系统，其在酸性肿瘤微环境下显示出聚集行为。该系统显著增强了对肿瘤细胞的磁致热治疗效果，并诱导肿瘤相关巨噬细胞(MAC)的M1极化和多核巨细胞(MGC)的形成，以实现免疫激活。这种受控的聚集系统实现了肿瘤几乎没有生长和转移的高度抑制作用，显示出改善MNPs基于恶化性癌症的磁致热治疗的有前途的策略。 ©作者（s）.

Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors. Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation. The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA). Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated. In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments. Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues. In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment. As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy. Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment. The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation. This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.© The author(s).