Recent advances in the development of tumor microenvironment-activatable nanomotors for deep tumor penetration

Abstract

Cancer represents a significant threat to human health, with the use of traditional chemotherapy drugs being limited by their harsh side effects. Tumor-targeted nanocarriers have emerged as a promising solution to this problem, as they can deliver drugs directly to the tumor site, improving drug effectiveness and reducing adverse effects. However, the efficacy of most nanomedicines is hindered by poor penetration into solid tumors. Nanomotors, capable of converting various forms of energy into mechanical energy for self-propelled movement, offer a potential solution for enhancing drug delivery to deep tumor regions. External force-driven nanomotors, such as those powered by magnetic fields or ultrasound, provide precise control but often necessitate bulky and costly external equipment. Bio-driven nanomotors, propelled by sperm, macrophages, or bacteria, utilize biological molecules for self-propulsion and are well-suited to the physiological environment. However, they are constrained by limited lifespan, inadequate speed, and potential immune responses. To address these issues, nanomotors have been engineered to propel themselves forward by catalyzing intrinsic "fuel" in the tumor microenvironment. This mechanism facilitates their penetration through biological barriers, allowing them to reach deep tumor regions for targeted drug delivery. In this regard, this article provides a review of tumor microenvironment-activatable nanomotors (fueled by hydrogen peroxide, urea, arginine), and discusses their prospects and challenges in clinical translation, aiming to offer new insights for safe, efficient, and precise treatment in cancer therapy.

Keywords: Arginine; Deep tumor penetration; Hydrogen peroxide; Nanomotors; Self-propelled; Urea.

Graphical abstract

Fig. 1

Timeline of discoveries and research on nanotechnology and tumor microenvironment-activated nanomotors. Milestone discoveries are highlighted. Nanotechnology research began in the 1960s. In the ensuing 40 years, nanotechnology has flourished, giving rise to the emergence of nanomotor technology [41,[45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59]].

Fig. 2

Nanomotor systems propelled by H₂O₂. (A) Preparation of BTS-Au@MnO₂ nanomotors and self-reported gas therapy. Reproduced with permission [84]. Copyright 2021, John Wiley & Sons. (B) Schematic representation of the assembly of micromotors with pH-responsive on/off motion. Note the relative size between each com ponent is not to scale. Reproduced with permission [86]. Copyright 2019, John Wiley & Sons. (C) Schematic diagram of magnetic field assistant tumor targeting of ISP-NMs and their ¹O₂ generation, movement and PDT process for cancer treatment. Reproduced with permission [88]. Copyright 2020, Elsevier.

Fig. 3

Nanomotor systems propelled by H₂O₂. (A) Schematic illustration showing the processes of ZIF-67 micromotors, ZIF67/Fe₃O₄/DOX multifunctional micromotors fabrication and the mechanism of drug delivery. Reproduced with permission [87]. Copyright 2018, Royal Society of Chemistry. (B)Supramolecular assembly of the enzyme-driven nanomotor. Reproduced with permission [92]. Copyright 2016, American Chemical Society. (C) Schematic illustrating the dual-source powered nanomotor for SERS biosensing and multimodal cancer photo-theranostics. Reproduced with permission [95]. Copyright 2022, Elsevier. (D) Schematic illustration of the cascade enzyme-powered nanomotor (NM-si) for TME modulation. Reproduced with permission [93]. Copyright 2021, Elsevier. (E) Schempatic Illustration of the Preparation of CREKA-Modified Ceria@Polydopamine Nanobowls (CREKA-Ce@ PDA NBs) and Their Application for Enhanced Tumor Penetration and Antitumor Effect. Reproduced with permission [94]. Copyright 2023, American Chemical Society.

Fig. 4

Nanomotor systems propelled by urea. (A) Schematic illustration for the intravesical delivery of urease-powered nanomotors to enhance penetration and retention in the bladder and the preparation procedure of urease (Ur) powered nanomotors using silica nanoparticle (SiNP) and polydopamine nanocapsule (PDA NC). Reproduced with permission [100]. Copyright 2020, American Chemical Society. (B) Schematic illustration of urease-driven urease robots targeting bladder cancer with radionuclides. Reproduced with permission [121]. Copyright 2020, Springer Nature. (C) Schematic diagram of enzyme-driven liquid metal nanorobots with dual-mode photoacoustic and ultrasound imaging for synergistic photothermal and chemotherapy antibacterial therapy. Reproduced with permission [102]. Copyright 2021, American Chemical Society. (D) Schematic diagram of a urease-driven nanomotor of mesoporous silica nanoparticles with polyethylene glycol and anti-FGFR3 antibody on the outer surface. Reproduced with permission [99]. Copyright 2018, American Chemical Society. (E) Preparation and characterization of HSiO₂ FA-Urease-I (Urease inside) and HSiO₂ Preparation and characterization of HSiO₂FA-Urease-I (Urease inside) and HSiO₂FA-Urease-O (Urease outside) micromotors. (a) Schematic diagram depicting the experimental process employed to fabricate HSiO₂FA-Urease-I and HSiO₂FA-Urease-O micromotors. Reproduced with permission [104]. Copyright 2021, American Chemical Society.

Fig. 5

Nanomotor systems propelled by arginine. (A) Synthetic Route of HFCA/DTX/aPD1 Nanomotor and the Schematic Illustration of Regulatory Mechanism of Combined Immunotherapy and Chemotherapy. Reproduced with permission [108]. Copyright 2021, American Chemical Society. (B) The fabrication process of HFLA-DOX nanomotors and the versatility of NO. Reproduced with permission [107]. Copyright 2020, John Wiley & Sons. (C) Schematic illustration of the formation of zwitterion-based nanomotor and the NO generation principle. Reproduced with permission [56]. Copyright 2019, Springer Nature.

Fig. 6

Schematic illustration of precision targeting nanomotors for tumor cells.