Researchers design a nanovaccine that detects MRSA toxins, kills bacteria with heat, and captures antigens to train the immune system for lasting protection.
(Nanowerk Spotlight) Infectious disease control is undergoing a fundamental shift as bacterial resistance outpaces drug development. Methicillin-resistant Staphylococcus aureus (MRSA), a pathogen linked to serious skin and soft tissue infections, bloodstream infections, and hospital outbreaks, remains especially difficult to eliminate. Treatment failure often arises not just from the pathogen’s ability to evade antibiotics but from its tendency to re-establish infection after initial clearance.
Conventional vaccines have proven largely ineffective against MRSA, with no candidates currently approved for human use. A central problem is that MRSA displays highly variable surface antigens. Subunit vaccines, which use specific bacterial components to stimulate immunity, frequently target only a narrow antigen set and lack the breadth needed to protect against diverse strains. Moreover, they struggle to generate durable immune memory.
Antibiotic therapy alone cannot solve this. Many bacterial strains form persistent colonies, invade host cells, or resist immune clearance. MRSA recurrence rates remain high, in some cases exceeding 40%. Nanotechnology has introduced promising alternatives.
Among them, photothermal therapy (PTT) stands out. This technique uses nanoparticles that convert near-infrared (NIR) light into localized heat, physically destroying bacteria without relying on chemical antibiotics. Yet PTT remains a local intervention. It kills bacteria effectively at the site of infection but does little to stimulate long-term immunity. Bacterial debris released during photothermal killing is quickly cleared and rarely elicits the immune memory necessary to prevent reinfection.
A research team based at Shanghai University, in collaboration with institutions in Switzerland and the United States, has developed a therapeutic strategy that addresses these limitations. In a study published in Advanced Functional Materials (“Toxin‐Responsive Antigen Reservoir Nanovaccines for In Situ Vaccination Against Bacterial Infection Recurrence”), the researchers report a nanoparticle system that combines targeted bacterial killing with antigen retention to generate lasting immune protection. This platform, called RBCM@PPPB, acts as both a photothermal agent and an in situ nanovaccine—delivering localized bacterial destruction while collecting and presenting antigens to the immune system.
Toxin-responsive “antigen reservoir” nanoparticles served as in situ therapeutic vaccines against bacterial infection recurrence. A) The fabrication of RBCM@PPPB nanoparticles. B) RBCM@PPPB nanoparticles experienced toxin-responsive disassembly of the RBCM layer and precise targeting to the MRSA surface, and further achieved bacteria-killing, antigen collection, and enhanced antigen presentation and subsequent immune memory based on the photoimmunotherapy (PIT) strategy. (Image: reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
The core of this system is a nanoparticle made from Prussian blue, a clinically approved material known for its high photothermal efficiency and biosafety. This core is coated with a polymer called polydopamine, which serves two purposes: it enhances the particle’s ability to absorb bacterial proteins and improves its photothermal properties. The surface is further functionalized with short peptides that bind specifically to MRSA. To ensure stealth and longevity in the bloodstream, the particle is cloaked in a layer of red blood cell membrane (RBCM), which disguises it from immune detection.
This outer membrane performs a second, more specialized function. MRSA secretes a pore-forming toxin known as α-toxin, which interacts with red blood cells during infection. When the nanoparticle encounters α-toxin, the RBCM layer disintegrates, revealing the underlying MRSA-targeting peptides. These peptides allow the particle to bind directly to MRSA at the infection site. Once attached, the particle can be activated with NIR light to generate heat, killing nearby bacteria.
Importantly, this process creates a source of bacterial debris—proteins, peptides, and other cellular fragments released from lysed MRSA. Rather than allowing these antigens to disperse, the polydopamine layer binds and holds them. This converts the nanoparticle into what the researchers describe as an “antigen reservoir,” capable of engaging the immune system and promoting the maturation of antigen-presenting cells such as dendritic cells.
In laboratory tests, the nanoparticle demonstrated high specificity for MRSA, binding preferentially to MRSA over E. coli in mixed cultures. The system’s responsiveness to α-toxin was confirmed both in vitro and in vivo. In mice bearing dual infections—MRSA on one side and either E. coli or α-toxin-deficient MRSA on the other—the particles accumulated only at the toxin-producing MRSA site. This selective accumulation is essential for minimizing damage to healthy tissue during NIR irradiation and maximizing the immune relevance of the antigens collected.
Thermal imaging confirmed that the particles generated sufficient heat upon NIR exposure to kill bacteria, reaching peak temperatures between 50 °C and 60 °C. Cell viability assays showed minimal cytotoxicity to mammalian cells, and hemolysis tests indicated that the particles remained non-destructive to red blood cells in the absence of bacterial toxins. The particles retained their photothermal performance over repeated heating cycles, suggesting they are stable enough for clinical translation.
Following photothermal treatment, the researchers investigated whether the accumulated bacterial debris could drive immune activation. RNA sequencing of MRSA treated with NIR-activated nanoparticles revealed upregulation of stress-related genes, including several that encode heat shock proteins—molecules known to act as immune danger signals. The debris also contained phenol-soluble modulins, key MRSA virulence factors and immunogenic targets. Polydopamine-coated particles absorbed over 90% of these proteins under test conditions.
The antigen-laden particles were then incubated with dendritic cells. Compared to controls, the treated cells showed significantly increased expression of surface markers CD80 and CD86, indicators of maturation and antigen presentation. Further gene expression analysis confirmed activation of immune signaling pathways, including toll-like receptors and IL-17-associated pathways, both critical for initiating adaptive responses.
Mouse experiments showed strong therapeutic benefits. In a skin abscess model, animals treated with the nanoparticles and NIR light showed accelerated wound healing, reduced inflammation, and near-total clearance of bacteria from infected tissue. Imaging revealed enhanced angiogenesis and tissue regeneration at the treatment site. Compared to vancomycin, a standard-of-care antibiotic for MRSA, the nanovaccine achieved greater bacterial elimination and, notably, induced adaptive immune responses.
Mice that received the nanovaccine displayed elevated levels of MRSA-specific helper T cells, cytotoxic T cells, and antibody-producing plasma cells. Serum antibody levels were significantly higher than in animals treated with vancomycin or left untreated. In a re-challenge experiment, mice that had previously received the nanovaccine resisted reinfection without developing new abscesses. Flow cytometry confirmed increased populations of memory T and B cells, both in the spleen and lymph nodes. These cells are responsible for recognizing pathogens upon secondary exposure and initiating rapid immune responses.
The authors note that while their model used localized intralesional injections, the design of the particle—especially its RBCM coating and moderate size—makes it a candidate for systemic administration. This could expand its application to bloodstream infections or other difficult-to-reach bacterial reservoirs. The platform is modular and could potentially be adapted to other pathogens by changing the targeting peptides.
Though the study demonstrates immune memory formation and pathogen clearance within a three-week timeframe, longer-term studies will be needed to confirm the durability of protection. Still, the integration of selective bacterial killing, antigen collection, and immune system engagement in a single nanoparticle system marks a significant technical step. The platform enables local bacterial destruction while preserving immunogenic debris, converting an antimicrobial event into an opportunity for in situ vaccination.
Get our Nanotechnology Spotlight updates to your inbox!
Thank you!
You have successfully joined our subscriber list.
Become a Spotlight guest author! Join our large and growing group of guest contributors. Have you just published a scientific paper or have other exciting developments to share with the nanotechnology community? Here is how to publish on nanowerk.com.
