As one of the most malignant tumors, metastatic melanoma essentially requires the regulation of the lysosomal cation channel, transient receptor potential mucolipin channel 1 (TRPML1), which is also involved in the participation of various ions, especially zinc ions. This perfectly aligns with the advanced therapeutic approach based on nanomaterials, because nanomaterials can easily integrate multiple metal elements to disrupt the internal homeostasis of various ions, eventually inhibiting the cell growth of metastatic melanoma. Hence, based on our previously proposed metalloptosis strategy, herein, zinc gallate-based nanoclusters (ZGOCs) containing both zinc and gallium were developed, capable of inducing metalloptosis. Responded to a weak-acid tumor microenvironment, ZGOCs could effectively release gallium ions that triggered ferroptosis through depleting glutathione and increasing lipid peroxidation levels. Moreover, the released zinc ions co-treated with ML-SA5, a TRPML-specific agonist, further promoted lysozincrosis. In addition, ZGOCs exhibited rechargeable afterglow luminescence, which facilitated in vivo clearer diagnostic images with high contrast for more accurate detection of tumor boundaries. Collectively, ZGOCs in combination with ML-SA5 significantly suppressed tumor growth with favorable biosafety, providing a promising metalloptosis-based strategy for the treatment of metastatic melanoma.

Microplastics can traverse human physiological barriers, infiltrate and accumulate in critical organs and tissues (e.g., brain, blood, and heart) over extended periods, posing significant threats to human health. While microplastic degradation in aquatic environments (e.g., contaminated water) has been extensively studied, research on bloodstream microplastic degradation remains largely unexplored, leaving a critical gap in remediation strategies. To fill this gap, we pioneered the fabrication of biocompatible magnetically driven Fe3O4@polydopamine (PDA)-lipase microrobots by functionalizing Fe3O4 nanoparticles with PDA and lipase for blood-borne microplastic degradation. In vitro blood experiments confirmed that this platform holds promise for future detoxification of circulating microplastics. The microrobots integrate synergistic functions: Fe3O4 enables magnetic responsiveness for precise movement control; PDA provides adhesive properties for robust microplastic binding; and lipase mediates enzymatic microplastic degradation. Guided by an external rotating magnetic field, the microrobots achieve targeted microplastic capture and in situ enzymatic degradation in blood without releasing harmful substances, addressing a pivotal safety concern for biomedical applications. Performance evaluations showed ~25% microplastic degradation efficiency in blood after 7 days of incubation. Additionally, the microrobots can be effectively recycled via magnetic separation postdegradation, reducing residuals and improving practicality. Hemolysis assays using rabbit blood and toxicity evaluations using human umbilical vein endothelial cells and immunofluorescence experiments confirmed their excellent biocompatibility and immunogenicity, an indispensable prerequisite for potential in vivo translation. As a proof-of-concept study, this work provides a promising biocompatible approach for blood microplastic degradation and clearance, simultaneously overcoming the technical challenge of blood-specific targeted degradation and meeting safety requirements, thus laying a foundation for microrobot-based mitigation of microplastic health hazards.

Postoperative metastatic recurrence and wound infection pose significant threats to survival after breast cancer (BC) surgery. To address these challenges, an ideal therapeutic strategy should incorporate minimally invasive multifunctional biomaterials capable of simultaneously preventing tumor recurrence and promoting wound healing. Herein, we report a novel 2-stage microneedle (MN) platform engineered via the integration of nanotechnology and tumor-microenvironment-responsive design. This system is fabricated using a stepwise casting strategy and features tip-to-base architecture equipped with on-demand smart nanocarriers for synergistic therapy against postoperative BC recurrence and wound complications. The MN consists of a photo-crosslinked hydrogel tip encapsulating chitosan-based self-assembled nanocarriers and a gelatin–polydopamine hydrogel backing layer. Owing to its hierarchical structural design, the MN exhibits excellent mechanical strength with a compression force of up to 4.48 N per needle, sufficient for efficient skin penetration. Moreover, the platform demonstrates sustained pH-responsive behavior and specific tumor microenvironment targeting, enabling controlled drug release. The MN also displays outstanding biocompatibility and multifunctional therapeutic properties, including antibacterial adhesion, self-healing capability, swelling performance, and biodegradability, greatly broadening its potential as a precision medicine tool. Both in vitro and in vivo studies validated the robust and integrated therapeutic efficacy of the MN system in suppressing metastatic BC recurrence and enhancing infected wound healing. This work provides a significant advance in the design of smart 2-stage MNs with comprehensive functionality for minimally invasive adjuvant therapy after BC surgery.