Stimuli-activatable strategies prevail in the design of nanomedicine for cancer theranostics. Upon exposure to endogenous/exogenous stimuli, the stimuli-activatable nanomedicine could be self-assembled, disassembled, or functionally activated to improve its biosafety and diagnostic/therapeutic potency. A myriad of tumor-specific features, including a low pH, a high redox level, and overexpressed enzymes, along with exogenous physical stimulation sources (light, ultrasound, magnet, and radiation) have been considered for the design of stimuli-activatable nano-medicinal products. Recently, novel stimuli sources have been explored and elegant designs emerged for stimuli-activatable nanomedicine. In addition, multi-functional theranostic nanomedicine has been employed for imaging-guided or image-assisted antitumor therapy. In this review, we rationalize the development of theranostic nanomedicine for clinical pressing needs. Stimuli-activatable self-assembly, disassembly or functional activation approaches for developing theranostic nanomedicine to realize a better diagnostic/therapeutic efficacy are elaborated and state-of-the-art advances in their structural designs are detailed. A reflection, clinical status, and future perspectives in the stimuli-activatable nanomedicine are provided.

Stimuli-activatable nanomedicine meets cancer theranostics

Two-dimensional (2D) materials are amongst the most interesting scientific research materials in the twenty-first century. 

Recent advances in MXenes: A future of nanotechnologies

Nanomedicines, emerging as an innovative category of cancer therapeutics, have garnered increasing attention from both researchers and the broader public. However, despite this surge in interest, a focused and comprehensive discussion highlighting their distinct advantages over small molecule drugs remains conspicuously absent. This knowledge gap not only piques the curiosity of the general audience but also leaves researchers engaged in these investigations with only partial insights, rather than a comprehensive understanding. This deficiency represents a critical juncture that demands earnest consideration. In light of this context, the present study endeavors to consolidate and elucidate the unique merits of nanomedicines, particularly in contrast to traditional small molecule drugs, within the realm of cancer treatment. We have meticulously summarized 14 distinct advantages of nanomedicine, alongside their recent and advanced applications, with a special focus on the past three years. Our objective is 2-fold: first, to provide researchers with a clear and comprehensive understanding that facilitates the precise design of nanomedicines, and second, to offer nonspecialists an accessible platform for grasping these concepts and establishing a strong foundation for widespread awareness. In essence, our study aims to bridge the gap in knowledge, shedding light on the unparalleled potential of nanomedicines in cancer therapy, and we believe that our findings hold great promise in advancing both scientific research and public understanding in this critical field. 

Advantages of Nanomedicine in Cancer Therapy: A Review

Due to ultralow defect formation energy, borophene differs significantly from other 2D (two-dimensional) materials in that it is difficult to distinguish between its crystal and boron (B) vacancy defect. In contrast to other 2D materials like graphene, borophene does not form layers when it is in its bulk state. In addition, borophene NM's atomic structure is different from graphene's in that it consists of connected triangles rather than hexagons. This atomic configuration has gaps where atoms are missing, resulting in a flaw called a "hollow hexagon" (HH). In borophene phases, these HHs can be found in a variety of ratios. The phase intermixing of borophene is a brand-new example of an 'ordered' defect discovered in 2D materials. The majority of 2D materials have flaws or disruptions to the atom arrangement at the boundaries between various domains or phases. Defects play a major influence in determining the properties of materials in a 2D system, because all atoms are virtually on the surface. For instance, the line defects along phase boundaries in borophene have no effect on the material's electrical characteristics at ambient temperature, in contrast to insulating flaws in metallic graphene. The atoms at the borders of borophene easily fit along line faults and adopt the configuration of their neighbors, causing no disruption. Additionally, the line flaws do not disrupt the seamless structure of borophene and maintain its stability and metallic properties. Experimentally, all four borophene phases have been synthesized, and they are all metallic. A list of borophene NM's special characteristics, including its negative Poisson's ratio and extremely anisotropic Young's modulus, is discussed. Here we also emphasized on B's conductive and superconductive qualities. An overview of borophene NM's uses in the energy sectors, including metal ion batteries, and supercapacitors (SCs), is covered in great length at the very end. 

Two dimensional borophene nanomaterials: Recent developments for novel renewable energy storage applications

Sonodynamic therapy (SDT) is an emerging non-invasive cancer treatment method in the field of nanomedicine, which has the advantages of deep penetration, good therapeutic efficacy, and minimal damage to normal tissues. Sonosensitizers play a crucial role in the process of SDT, as their structure and properties directly determine the treatment outcome. Inorganic sonosensitizers, with their high stability and longer circulation time in the human body, have great potential in SDT. In this review, the possible mechanisms of SDT including the ultrasonic cavitation, reactive oxygen species generation, and activation of immunity are briefly discussed. Then, the latest research progress on inorganic sonosensitizers is systematically summarized. Subsequently, strategies for optimizing treatment efficacy are introduced, including combination therapy and image-guided therapy. The challenges and future prospects of sonodynamic therapy are discussed. It is hoped that this review will provide some guidance for the screening of inorganic sonosensitizers.

A Comprehensive Review of Inorganic Sonosensitizers for Sonodynamic Therapy

Ultrasound (US) is considered as a secure external stimulation for different biomedical applications because it is non-invasive, non-toxic and it brings no radiation pollution. Compared with traditional ultrasonography application, US has now attracted more and more attention for cancer therapy. It treats cancer in deeper tissues because it penetrates far than light does. New types of nanomaterials have been developed for US triggered cancer therapy. The study on emerging cancer therapeutic modality triggered by US is also increasing, e.g., high intensity-focused ultrasound (HIFU) therapy, sonodynamic therapy (SDT), and US-mediated drug delivery. The research on current advances in nanomaterials-based and US-triggered cancer treatments have been discussed in detail in this review, especially the underlying mechanisms for better therapeutic effectiveness. Furthermore, challenges and prospective in the evolution of nanomaterials for the US-based cancer therapy fields were also explained. It is anticipated that our manifestation in this expanding discipline will aid in the advancement of US-based basic research and therapeutic applications. 

Ultrasound combined with nanomaterials for cancer therapy

Photo-responsive NIR-II biomimetic nanomedicine for efficient cancer-targeted theranostics

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed. 

Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles.

It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532 exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532 efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532 provides a new approach for potentially safer and more effective treatment of AS in the future.

Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

Editor’s note to “Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles” [Biomed. Pharmacother. 172 (2024) 116221]

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