Most nanoparticles for biomedical applications originate from the self-assembling of individual constituents through molecular interactions and possess limited geometry control and stability. Here, 1000 × 400 nm discoidal polymeric nanoconstructs (DPNs) are demonstrated by mixing hydrophobic and hydrophilic polymers with lipid chains and curing the resulting paste directly within silicon templates. By changing the paste composition, soft- and rigid-DPNs (s- and r-DPNs) are synthesized exhibiting the same geometry, a moderately negative surface electrostatic charge (-14 mV), and different mechanical stiffness (∼1.3 and 15 kPa, respectively). Upon injection in mice bearing nonorthotopic brain or skin cancers, s-DPNs exhibit ∼24 h circulation half-life and accumulate up to ∼20% of the injected dose per gram tumor, detecting malignant masses as small as ∼0.1% the animal weight via PET imaging. This unprecedented behavior is ascribed to the unique combination of geometry, surface properties, and mechanical stiffness which minimizes s-DPN sequestration by the mononuclear phagocyte system. Our results could boost the interest in using less conventional delivery systems for cancer theranosis.

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Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging; guidance under remote fields; heat generation; and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ~10 times (r2 ~ 835 (mM·s)−1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r2 relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ~ 65 fg) and the consequent generation of significant inter-particle magnetic dipole interactions. In tumor bearing mice, the silicon-based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (~ 0.5 mg of Fe/kg animal) as compared to current practice.

Aminobisphosphonates, such as zoledronic acid (ZA), have shown potential in the treatment of different malignancies, including colorectal carcinoma (CRC). Yet, their clinical exploitation is limited by their high bone affinity and modest bioavailability. Here, ZA is encapsulated into the aqueous core of spherical polymeric nanoparticles (SPNs), whose size and architecture resemble that of biological vesicles. On Vδ2 T cells, derived from the peripheral blood of healthy donors and CRC patients, ZA-SPNs induce proliferation and trigger activation up to three orders of magnitude more efficiently than soluble ZA. These activated Vδ2 T cells kill CRC cells and tumor spheroids, and are able to migrate toward CRC cells in a microfluidic system. Notably, ZA-SPNs can also stimulate the proliferation of Vδ2 T cells from the tumor-infiltrating lymphocytes of CRC patients and boost their cytotoxic activity against patients’ autologous tumor organoids. These data represent a first step toward the use of nanoformulated ZA for immunotherapy in CRC patients.