Tumor microenvironment-responsive spherical nucleic acid nanoparticles for enhanced chemo-immunotherapy.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Chemotherapeutics can induce immunogenic cell death (ICD), releasing tumor antigens to stimulate antitumor immunity.
• Co-delivery of adjuvants with nanocarriers can amplify ICD-induced immunity for synergistic chemo-immunotherapy.
• Challenges include complex preparation, low drug loading, and carrier toxicity, limiting clinical use.

Purpose of the Study:

• To develop a carrier-free nanoparticle system for enhanced chemo-immunotherapy.
• To improve drug accumulation and targeted release in the tumor microenvironment (TME).
• To boost ICD-induced antitumor immunity and reduce off-target toxicity.

Main Methods:

• Fabrication of core-shell nanoparticles (MPLA-CpG-sMMP9-DOX, MCMD NPs) via self-assembly of spherical nucleic acids (SNA).
• Core composed of dual adjuvants (CpG ODN and monophosphoryl lipid A - MPLA) within SNA.
• Shell comprised of doxorubicin (DOX) radially arranged around the core, with MMP-9 cleavable peptides.

Main Results:

• MCMD NPs enhanced drug accumulation in tumors and enabled enzyme-triggered DOX release in the TME.
• DOX release via MMP-9 degradation amplified direct tumor cell killing.
• The MPLA-CpG SNA core effectively boosted ICD-induced antitumor immune responses.
• Synergistic chemo-immunotherapy was achieved with reduced off-target toxicity.

Conclusions:

• Carrier-free MCMD NPs offer an efficient strategy for cancer chemo-immunotherapy.
• The system enhances therapeutic efficacy by combining chemotherapy and immunotherapy.
• This approach minimizes carrier-associated toxicity, paving the way for clinical applications.