Superparamagnetic iron oxide (SPIO) nanoparticles have been extensively employed for theranostic applications due to their good biocompatibility and excellent magnetic resonance imaging (MRI) properties. However, these particles typically require surface modification due to their hydrophobic surfaces caused by the oil-phase surfactants used in the fabrication and thus, the drug loading on their surface is usually limited. Here, we provided a novel and facile approach to conveniently perform surface modification of SPIO while simultaneously loading a large amount of drug. By synthesizing an amphiphilic irinotecan-based compound with a hydrophobic tail enabling insertion into the SPIO assembly, an excellent SPIO-based theranostic nanomedicine (SPIO@IR) was produced. SPIO@IR not only extensively improved the drug efficacy, but also allowed visualization by MRI in biological systems.

Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. However, targeted delivery of nanotheranostics is hindered by several biological barriers. Here, we report the development of a dual size/charge- transformable, Trojan-Horse nanoparticle (pPhD NP) for delivery of ultra-small, full active pharmaceutical ingredients (API) nanotheranostics with integrated dual-modal imaging and trimodal therapeutic functions. pPhD NPs exhibit ideal size and charge for drug transportation. In tumour microenvironment, pPhD NPs responsively transform to full API nanotheranostics with ultra-small size and higher surface charge, which dramatically facilitate the tumour penetration and cell internalisation. pPhD NPs enable visualisation of biodistribution by near-infrared fluorescence imaging, tumour accumulation and therapeutic effect by magnetic resonance imaging. Moreover, the synergistic photothermal-, photodynamic- and chemo-therapies achieve a 100% complete cure rate on both subcutaneous and orthotopic oral cancer models. This nanoplatform with powerful delivery efficiency and versatile theranostic functions shows enormous potentials to improve cancer treatment.

Gadolinium-based contrast agents (GBCAs) are the most widely used T₁ contrast agents for magnetic resonance imaging (MRI) and have achieved remarkable success in clinical cancer diagnosis. However, GBCAs could cause severe nephrogenic systemic fibrosis to patients with renal insufficiency. Nevertheless, GBCAs are quickly excreted from the kidneys, which shortens their imaging window and prevents long-term monitoring of the disease per injection. Herein, a nephrotoxicity-free T₁ MRI contrast agent is developed by coordinating ferric iron into a telodendritic, micellar nanostructure. This new nano-enabled, iron-based contrast agent (nIBCA) not only can reduce the renal accumulation and relieve the kidney burden, but also exhibit a significantly higher tumor to noise ratio (TNR) for cancer diagnosis. In comparison with Magnevist (a clinical-used GBCA), Magnevist induces obvious nephrotoxicity while nIBCA does not, indicating that such a novel contrast agent may be applicable to renally compromised patients requiring a contrast-enhanced MRI. The nIBCA could precisely image subcutaneous brain tumors in a mouse model and the effective imaging window lasted for at least 24 h. The nIBCA also precisely highlights the intracranial brain tumor with high TNR. The nIBCA presents a potential alternative to GBCAs as it has superior biocompatibility, high TNR and effective imaging window.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (T_eff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/T_eff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α₃β₁ integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures T_eff cells via the activatable α₄β₁ integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.