Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.

The facile preparation, modular design, and multi‐responsiveness are extremely critical for developing pervasive nanoplatforms to meet heterogeneous applications. Here, cationic nanogels (NGs) are modularly engineered with tunable responsiveness, versatility, and biodegradation. Cationic PVCL‐based NGs with core/shell structure are fabricated by facile one‐step synthesis. The formed PVCL‐NH₂ NGs exhibit uniform size, thermal/pH dual‐responsive behaviors, and redox‐triggered degradation. Moreover, the NGs can be employed to modify or/and load with various functional agents to construct multipurpose nanoplatforms in a modular manner. Notably, the novel hybrid structure with copper sulfide (CuS) NPs loaded in the NGs shell is prepared, which leads to higher photothermal conversion efficiency (31.1%) than other CuS randomly loaded NGs reported. By personalized tailoring, these functionalized NGs display fluorescent property, r₁ relaxivity, strong near‐infrared (NIR) absorption, good biocompatibility, and targeting specificity. The superior photothermal effect of hybrid NGs (CuS@NGs‐LA) is presented under NIR II over NIR I. Importantly, hybrid NGs encapsulated doxorubicin (CuS@NGs‐LA/DOX) show endogenous pH/redox and exogenous NIR multi‐triggered drug release for efficient photothermal‐chemotherapy, which can completely eliminate advanced tumors and effectively inhibit recurrence. Overall, the pervasive nanoplatforms based on intelligent cationic NGs with tunable responsiveness, versatility, and biodegradation are developed by engineered modular strategy for precision medicine applications.

Nanocarriers (NCs) play a crucial role in delivering theranostic agents to tumors, making them a pivotal focus of research. However, the persistently low delivery efficiency of engineered NCs has been a significant challenge in the advancement of nanomedicine, stirring considerable debate. Transvascular transport is a critical pathway for NC delivery from vessels to tumors, yet a comprehensive understanding of the interactions between NCs and vascular systems remains elusive. In recent years, considerable efforts have been invested in elucidating the transvascular transport mechanisms of NCs, leading to promising advancements in tumor delivery and theranostics. In this context, we highlight various delivery mechanisms, including the enhanced permeability and retention effect, cooperative immune-driven effect, active transcytosis, and cell/bacteria-mediated delivery. Furthermore, we explore corresponding strategies aimed at enhancing transvascular transport of NCs for efficient tumor delivery. These approaches offer intriguing solutions spanning physicochemical, biological, and pharmacological domains to improve delivery and therapeutic outcomes. Additionally, we propose a forward-looking delivery framework that relies on advanced tumor/vessel models, high-throughput NC libraries, nano-bio interaction datasets, and artificial intelligence, which aims to guide the design of next-generation carriers and implementation strategies for optimized delivery.

Development of multifunctional theranostic nanoplatforms with improved diagnostic sensitivity and therapeutic efficiency of tumors still remains a great challenge. A unique multifunctional theranostic nanoplatform based on generation 5 (G5) poly(amidoamine) dendrimer–stabilized gold nanoflowers (NFs) embedded with ultrasmall iron oxide (USIO) nanoparticles (NPs) for multimode T₁‐weighted magnetic resonance (MR)/computed tomography (CT)/photoacoustic (PA) imaging–guided combination photothermal therapy (PTT) and radiotherapy (RT) of tumors is reported here. G5 dendrimer–stabilized Au NPs and citric acid–stabilized USIO NPs are separately prepared, the two particles under a certain Fe/Au molar ratio are mixed to form complexes, the complexes are exposed to Au growth solution to form NFs via a seed–mediated manner, and the remaining dendrimer terminal amines are acetylated. The formed dendrimer‐stabilized Fe₃O₄/Au NFs (for short, Fe₃O₄/Au DSNFs) have a mean diameter of 99.8 nm, display good colloidal stability and cytocompatibility, and exhibit a near‐infrared absorption feature. The unique structure and composition of the Fe₃O₄/Au DSNFs endows them with a high r₁ relaxivity (3.22 mM⁻¹ s⁻¹) and photothermal conversion efficiency (82.7%), affording their uses as a theranostic nanoplatform for multimode MR/CT/PA imaging and combination PTT/RT of tumors with improved therapeutic efficacy, which is important for translational nanomedicine applications.